System and Method for Estimating Cardiac Pressure Based on Cardiac Electrical Conduction Delays Using an Implantable Medical Device

ABSTRACT

Techniques are provided for estimating left atrial pressure (LAP) or other cardiac performance parameters based on measured conduction delays. In particular, LAP is estimated based interventricular conduction delays. Predetermined conversion factors stored within the device are used to convert the various the conduction delays into LAP values or other appropriate cardiac performance parameters. The conversion factors may be, for example, slope and baseline values derived during an initial calibration procedure performed by an external system, such as an external programmer. In some examples, the slope and baseline values may be periodically re-calibrated by the implantable device itself. Techniques are also described for adaptively adjusting pacing parameters based on estimated LAP or other cardiac performance parameters. Still further, techniques are described for estimating conduction delays based on impedance or admittance values and for tracking heart failure therefrom.

RELATED APPLICATIONS

This application is related to U.S. patent application Ser. No. ______(Attorney Docket No. A07P3015-US2) of Wenzel et al., entitled, “Systemand Method for Estimating Cardiac Pressure Based on Cardiac ElectricalConduction Delays Using An Implantable Medical Device,” filedconcurrently with this application. This application also claimspriority on U.S. Provisional Patent Application No. 60/910,060 of Wenzelet al., entitled, “System and Method for Estimating Left Atrial Pressurebased on Intra-Cardiac Conduction Time Delays,” filed Apr. 4, 2007,which is fully incorporated by reference herein.

FIELD OF THE INVENTION

The invention relates generally to implantable medical devices such aspacemakers and implantable cardioverter defibrillators (ICDs) and inparticular to techniques for estimating cardiac pressure (particularlyleft atrial pressure (LAP)) to detect and evaluate heart failure andrelated conditions and to automatically adjust pacing parameters or thelike.

BACKGROUND OF THE INVENTION

Heart failure is a debilitating disease in which abnormal function ofthe heart leads to inadequate blood flow to fulfill the needs of thetissues and organs of the body. Typically, the heart loses propulsivepower because the cardiac muscle loses capacity to stretch and contract.Often, the ventricles do not adequately fill with blood betweenheartbeats and the valves regulating blood flow become leaky, allowingregurgitation or back-flow of blood. The impairment of arterialcirculation may deprive vital organs of oxygen and nutrients. Fatigue,weakness and the inability to carry out daily tasks may result. Not allheart failure patients suffer debilitating symptoms immediately. Somemay live actively for years. Yet, with few exceptions, the disease isrelentlessly progressive. As heart failure progresses, it tends tobecome increasingly difficult to manage. Even the compensatory responsesit triggers in the body may themselves eventually complicate theclinical prognosis. For example, when the heart attempts to compensatefor reduced cardiac output, it adds cardiac muscle mass causing theventricles to grow in volume in an attempt to pump more blood with eachheartbeat, i.e. to increase the stroke volume. This places a stillhigher demand on the heart's oxygen supply. If the oxygen supply fallsshort of the growing demand, as it often does, further injury to theheart may result, typically in the form of myocardial ischemia ormyocardial infarction. The additional muscle mass may also stiffen theheart walls to hamper rather than assist in providing cardiac output.Often, electrical and mechanical dyssynchronies develop within the heartsuch that the various chambers of the heart no longer beat in asynchronized manner, degrading overall cardiac function. A particularlysevere form of heart failure is congestive heart failure (CHF) whereinthe weak pumping of the heart or compromised filling leads to build-upof fluids in the lungs and other organs and tissues.

Many patients susceptible to CHF, particularly the elderly, havepacemakers, ICDs or other implantable medical devices implanted therein,or are candidates for such devices. Accordingly, it is desirable toprovide techniques for detecting and tracking CHF using such devices.One particularly effective parameter for detecting and tracking CHF iscardiac pressure, particularly LAP, i.e. the blood pressure within theleft atrium of the patient. Reliable detection or estimation of LAPwould not only permit the implanted device to track CHF for diagnosticpurposes but to also control therapies applied to address CHF such ascardiac resynchronization therapy (CRT). CRT seeks to normalizeasynchronous cardiac electrical activation and the resultantasynchronous contractions by delivering synchronized pacing stimulus tothe ventricles using pacemakers or ICDs equipped with biventricularpacing capability. The pacing stimulus is typically synchronized so asto help to improve overall cardiac function. This may have theadditional beneficial effect of reducing the susceptibility tolife-threatening tachyarrhythmias. CRT and related therapies arediscussed in, for example, U.S. Pat. No. 6,643,546 to Mathis, et al.,entitled “Multi-Electrode Apparatus And Method For Treatment OfCongestive Heart Failure”; U.S. Pat. No. 6,628,988 to Kramer, et al.,entitled “Apparatus And Method For Reversal Of Myocardial RemodelingWith Electrical Stimulation”; and U.S. Pat. No. 6,512,952 to Stahmann,et al., entitled “Method And Apparatus For Maintaining SynchronizedPacing”.

Reliable estimates of LAP provided by a pacemaker or ICD would alsoallow the dosing of heart failure medications (such as diuretics) to beproperly titrated so as to minimize the number of episodes of acuteheart failure decompensation. Another advantage to providing reliableestimates of LAP is that physicians are typically familiar with LAPvalues. Hence, LAP estimates could be provided to the physician viadiagnostic displays, which the physicians can then readily interpret.

However, LAP is a difficult parameter to detect since it is notclinically appealing to place a blood pressure sensor directly in theleft atrium due to the chronic risk of thromboembolic events, as well asrisks associated with the trans-septal implant procedure itself.Accordingly, various techniques have been developed for estimating LAPbased on other parameters that can be more safely sensed by a pacemakeror ICD. In this regard, a number of techniques have been developed thatuse electrical impedance signals to estimate LAP. For example, impedancesignals can be sensed along a sensing vector passing through the leftatrium, such as between an electrode mounted on a left ventricular (LV)lead and another electrode mounted on a right atrial (RA) lead. Thesensed impedance is affected by the blood volume inside the left atrium,which is in turn reflected by the pressure in the left atrium.Accordingly, there is a correlation between the sensed impedance andLAP, which can be exploited to estimate LAP and thereby also track CHF.See, for example, U.S. Provisional Patent Application No. 60/787,884 ofWong et al., entitled, “Tissue Characterization Using IntracardiacImpedances with an Implantable Lead System,” filed Mar. 31, 2006, andU.S. patent application Ser. Nos. 11/558,101, 11/557,851, 11/557,870,11/557,882 and 11/558,088, each entitled “Systems and Methods to Monitorand Treat Heart Failure Conditions”, of Panescu et al. See, also, U.S.patent application Ser. No. 11/558,194, by Panescu et al., entitled“Closed-Loop Adaptive Adjustment of Pacing Therapy based on CardiogenicImpedance Signals Detected by an Implantable Medical Device.”Particularly effective techniques for calibrating impedance-basedtechniques are set forth in: U.S. patent application Ser. No.11/559,235, by Panescu et al., entitled “System and Method forEstimating Cardiac Pressure Using Parameters Derived from ImpedanceSignals Detected by an Implantable Medical Device.”

It would be desirable to develop LAP estimation techniques that do notrely only impedance but instead, or additionally, exploit intracardiacelectrogram (IEGM) signals commonly sensed by pacemakers and ICDs, andit is to that end that certain aspects of the present invention aredirected. Also, it would be desirable to provide techniques forautomatically adjusting and controlling CRT and other forms of cardiacrhythm management therapy in response to estimated LAP so as to, e.g.,mitigate the effects of CHF, and it is to that end that other aspects ofthe present invention are directed.

SUMMARY OF THE INVENTION

In accordance with an exemplary embodiment, a method and system areprovided for estimating cardiac pressure within a patient using animplantable medical device. Briefly, an electrical conduction delay ismeasured in the heart of the patient that is affected by cardiacpressure. Then, cardiac pressure is estimated within the patient basedon the conduction delay. In this regard, when a particular chamber ofthe heart is stimulated, cardiac contraction occurs in the stimulatedchamber, and this is usually followed by a subsequent cardiaccontraction in other chamber(s) later in time after the stimulus has hadsufficient time to reach the other chamber(s). The conduction time delaybetween contractions of any two chambers is dependent on variousfactors, such as conduction velocity and the distance needed to betraveled. The conduction time delay between the contraction of any twocardiac chambers following either a natural occurring stimulus or anexternally administered stimulus is indicative, in at least somepatients, of the degree of cardiac failure, such that longer delays maybe associated with a worsening cardiac status. Moreover, the conductiontime delay is, in at least some patients, proportional to the cardiacchamber size and further indicative of the intracardiac chamberpressure, such that the conduction time delay may be advantageouslyexploited to estimate or predict the intra-cardiac chamber pressure, atleast within such patients.

In one example, conduction delays from the left ventricle (LV) to theright ventricle (RV) are measured by applying a cardiac pacing pulse(i.e. a V-pulse) to the LV using one or more LV electrodes and thensensing the subsequent electrical depolarization in the RV using one ormore RV electrodes. The intrinsic electrical depolarization in the RVmay be detected based on the timing of a QRS-complex sensed within an RVIEGM. The delay between the V-pulse delivered to the LV and the peak ofthe RV QRS-complex is then taken as an estimate of the LV-RVinterventricular conduction delay. In another example, conduction delaysfrom the LV to the RV are measured by sensing an intrinsic QRS-complexin both an LV IEGM and an RV IEGM. The delay between the LV QRS-complexand the RV QRS-complex is taken as the estimate of the LV-RVinterventricular conduction delay. In other examples, the RV is pacedfirst and the delay from the RV to the LV is measured. In still otherexamples, rather than using LV-RV delays, other AV delays are employed.For example, AV delays may be obtained based on paced or sensed eventsor based on P-wave morphology (e.g. based on the shape or width of theP-wave) or based on the morphology of atrial evoked responses.

Predetermined conversion factors are then input from memory forconverting the measured conduction delay to LAP values or other cardiacpressure values. The conversion factors may be, for example, slope andbaseline values derived using, e.g., linear regression techniques. Then,LAP or other cardiac pressure values are estimated within the patient byapplying the conversion factors to the conduction delay. For example,cardiac pressure may estimated using:

Cardiac Pressure=Delay*Slope+Baseline

where Delay is the measured conduction delay and Slope and Baseline arethe conversion factors appropriate to the pressure value being estimatedand the chambers through which the conduction delay is measured. For thecase where LAP is estimated from the LV-RV conduction delay:

qLAP _(LV-RV) =D _(LV-RV)*Slope_(LAP/LV-RV)+Baseline_(LAP/LV-RV)

where D_(LV-RV) is the measured conduction delay between the LV and theRV, Slope_(LAP/LV-RV) and Baseline_(LAP/LV-RV) are the conversionfactors appropriate to LAP when estimated based on the LV-RV conductiondelay, and qLAP_(LV-RV) is the resulting estimate of LAP. Note that thebaseline value will be in units of LAP. The LV-RV subscript is appliedso as to distinguish baseline values for use in estimating LAP fromLV-RV delays from other baseline values for use in estimating LAP basedon other delays. However, it should be understood that the use of suchsubscripts is an arbitrary terminology choice and hence has no effect onthe scope of the claimed subject matter. The “q” of qLAP is employed todistinguish the resulting estimate from the estimates made using theimpedance-based techniques discussed above in the Panescu et al. patentapplications (i.e. ZLAP estimates or eLAP.) Again, it should beunderstood that the use of the term “qLAP” is an arbitrary terminologychoice and hence has no effect on the scope of the claimed subjectmatter. In many of the illustrative examples described herein, aQuickOpt technique is employed to determine the conduction delays.QuickOpt is a trademark of St. Jude Medical. QuickOpttechniques aredescribed more fully in U.S. Patent Application No. 2005/0125041 of Minet al., published Jun. 9, 2005, entitled “Methods for VentricularPacing.” The subscript “LV-RV” is applied to qLAP to indicate that theestimate is derived from an LV-RV conduction delay. LAP may potentiallybe estimated from other conduction delay values as well, such as AVdelays.

The pressure value estimated in the foregoing example (and in the otherexamples described herein) is an effective intracardiac pressure(P_(eff)), not an absolute pressure. It represents the absoluteintracardiac pressure less intrathoracic pressure:

P _(eff) =P _(intracardiac) −P _(intrathoracic)

That is, the effective pressure is a type of gauge pressure. Unlessotherwise noted, all estimated cardiac pressure values discussed herein,particularly estimated LAP, are effective pressure values. In sometechniques described herein, such as techniques where the Valsalvamaneuver is exploited to reduce intracardiac pressure within the patientfor the calibration purposes, the distinction between effective pressureand absolute pressure is particularly important and effective pressureshould be used. In those examples, the term effective qLAP will be usedas a reminder that effective pressures are used. In any case, effectivepressure values are typically more useful from a clinical perspectivethan absolute pressure values.

In an illustrative example, the slope and baseline values(Slope_(LAP/LV-RV) and Baseline_(LAP/LV-RV)) are determined during aninitial calibration procedure based on the assumption that there is alinear relationship between D_(LV-RV) and LAP. To calibrate the slopeand baseline values for a particular patient, a first delay calibrationvalue (D_(LV-RV/1)) and a corresponding first cardiac pressurecalibration value (LAP₁) are measured within the patient at a firstpoint in time. Then, a second delay calibration value (D_(LV-RV/2)) anda corresponding second cardiac pressure calibration value (LAP₂) aremeasured at a second point time within the patient. The first and secondpressure calibration values (LAP₁, LAP₂) may be measured within thepatient using, e.g., a Swan-Ganz catheter equipped to measure pulmonarycapillary wedge pressure (PCWP). The times are chosen such that thefirst and second cardiac pressure values (LAP₁, LAP₂) differsubstantially from one another (and so the conduction delay values alsodiffer substantially from one another). In one particular example, thefirst pair of calibration values (D_(LV-RV/1), LAP₁) are detected whilethe patient is at rest; whereas the second calibration values(D_(LV-RV/2), LAP₂) are detected while the patient is subject to acondition significantly affecting cardiac pressure, such as isometricmuscle contraction, vasodilatation, vasoconstriction, rapid pacing orperformance of the Valsalva maneuver or the handgrip maneuver by thepatient. The slope value is then calibrated by calculating:

Slope_(LAP/LV-RV)=(LAP ₂ −LAP ₁)/(D _(LV-RV/2) −D _(LV-RV/1)).

The baseline value is calibrated by calculating:

Baseline_(LAP/LV-RV=) LAP ₂−Slope_(LAP/LV-RV) *D _(LV-RV/1).

Alternatively, a plurality of calibration values can instead be obtainedwithin the patient, with the slope and baseline values then calculatedfor that particular patient using linear regression techniques. In stillother implementations, calibration values are instead obtained withintest subjects, with the calibration values then employed to estimate LAPwithin other patients. For example, a plurality of calibration valuescan be obtained within a population of test subjects (particularly onesin which heart failure is progressing), with the slope and baselinevalues then calculated using linear regression techniques from the dataobtained from the test subjects. By using test subjects in which heartfailure is progressing, LAP likewise increases within the test subjects,yielding a range of pressure values suitable for linear regressionanalysis. The slope and baseline values obtained from the test subjectscan be used, at least, as starting values for use in estimating LAPwithin other patients, with those parameters then potentially optimizedfor use in the particular patient. Still further, linear models relatingcardiac pressure and conduction delays need not necessarily be used,i.e. more sophisticated correlation models may instead by used such asneural networks. Linear models are preferred in view of theirsimplicity.

The baseline value, once determined, may change over time within aparticular patient. Accordingly, it may be desirable within somepatients to occasionally re-calibrate the baseline value. Tore-calibrate the baseline value, an additional conduction delaycalibration value (D_(LV-RV/N)) is measured while the patient performs aValsalva maneuver. During the Valsalva maneuver, the chambers of theheart are substantially emptied of blood such that the effective cardiacblood pressure, particularly effective LAP or effective right atrialpressure (RAP), is reduced to near zero secondary to reduced venousreturn, especially in patients that have at rest moderate to low cardiacfilling pressures (<20 mmHg) with the absence of significant diastolicdysfunction or non-compliance of the heart. Under the assumption thatthe effective LAP drops to zero in the late Phase II of the Valsalvamaneuver (i.e., during the interval from 5 seconds to 10 secondsfollowing the initiation of the strain), the baseline value to beupdated by the implanted device using only the newly detected conductiondelay value, i.e. (Baseline_(LAP/LV-RV)) may be updated using:

Baseline_(LAP/LV-RV)=−Slope_(LAP/LV-RV) *D _(LV-RV/N).

In other implementations, both the slope and baseline values arere-calibrated by the implanted device based on newly detected conductiondelay values. In still other implementations, to account for the factthat the effective LAP does not reach zero completely during theValsalva maneuver in some patients (such as heart failure patients withhigh cardiac filling pressures >20 mmHg and/or with poor cardiaccompliance), an additional correction term may be obtained duringinitial calibration that is used to correct or adjust the re-calibratedvalues. Preferably, re-calibration is performed while the patient isclinically stable. Moreover, in at least some patients, Valsalva-basedre-calibration techniques may not achieve precise calibration due tothese factors. Within those patients, other re-calibration techniquesare preferably used, which do not necessarily exploit the Valsalvamaneuver. In general, any maneuver or condition that significantlyaffects cardiac pressure within the patient might be exploited forre-calibration purposes. Examples include one or more of: isometricmuscle contraction, vasodilatation, vasoconstriction, rapid pacing andperformance of the handgrip maneuver. The handgrip maneuver tends toacutely increase LAP. See, e.g., Helfant et al., “Effect of SustainedIsometric Handgrip Exercise on Left Ventricular Performance,”Circulation. 1971;44:982. LAP may be detected estimated using theSwan-Ganz catheter. In some cases, it may be appropriate to employmultiple re-recalibration techniques each yielding new Slope andBaseline values, which are then averaged together to yield there-calibrated values.

Also, in the illustrative example, therapy is controlled based on theestimated LAP (e.g. based on qLAP), particularly so as to reduce LAP.The therapy to be adjusted may be pacing therapy. For example, pacingtiming parameters such as the atrioventricular (AV) pacing delay and theinterventricular (LV-RV) pacing delay may be adjusted. Within systemsequipped to provide pacing at different locations within the samechamber, intraventricular (LV₁-LV₂), intra-atrial (LA₁-LA₂) delay valuesmay additionally or alternatively be adjusted. Alternatively, multi-sitepacing systems could switch to different pacing configurations or usedifferent pacing electrodes in order to keep the LAP estimate, qLAP,within a safe or hemodynamically stable range. Preferably, theadjustments are adaptive, i.e. the adjustments are performed in aclosed-loop so as to adapt the adjustments to changes in estimated LAPso as to optimize therapy. By adjusting pacing parameters based onestimated of LAP, the parameters can be promptly adjusted to immediatelyrespond to changes within the heart that affect LAP, such as anydeterioration in mechanical synchrony arising due to CHF, conductiondefects or other ailments such as myocardial infarction or acute cardiacischemia. Moreover, by adaptively adjusting the pacing parameters basedon estimated LAP, the direction and/or magnitude of the adjustments neednot be pre-determined. That is, it need not be known in advance whethera particular pacing parameter should be increased or decreased inresponse to deterioration in LAP. Adaptive adjustment allows thedirection and magnitude of any adjustments to the pacing parameters tobe automatically optimized. Thus, if an initial increase in a particularpacing parameter causes a further deterioration in LAP, the pacingparameter may then be automatically decreased in an attempt to improveLAP. If neither an increase nor a decrease in a particular pacingparameter significantly affects LAP, then a different pacing parametermay be selected for adaptive adjustment.

The adaptive adjustment of pacing therapy using estimated LAP may beperformed in conjunction with one or more impedance-based adjustmentstechniques, such as those set forth in the above-cited applications ofPanescu et al. For example, a mechanical dyssynchrony may derived fromthe cardiogenic impedance signals while an estimate of LAP is derivedfrom conduction delays, permitting both to be used in adjusting thepacing parameters. Also, impedance signals may be used to deriveelectrical conduction delays from which LAP may be also estimated. Stillfurther, if the implanted device may be equipped with a sensor todirectly measure another cardiac pressure value besides LAP (e.g., LVend diastolic (LV_(END)) pressure), then such pressure measurements maybe used in conjunction with the LAP estimates to adjust pacingparameters so as to reduce both measures of pressure. In someimplementations, the pacing parameters are adaptively adjusted only whenthe patient is in certain predetermined states as determined by activitysensor, posture detectors, etc. In one particular example, adaptiveadjustment is only performed if the patient is at rest and in a supineposture. Adaptive adjustment may be still further limited to times whenthe blood oxygen saturation (SO₂) level of the patient is within acertain acceptable range. Yet as a different embodiment, admittance orimpedance measurements could be used to estimate AV or VV delays. As theheart tends to enlarge with heart failure progression, conduction delaystend to increase whereas impedance values tend to decrease. Therefore,admittance or values could be used to estimate AV or VV delays. Acalibration step may be required depending upon the implementation. Ifrequired, calibration consists of determining delays using knowntechniques (such as based on electrograms, as presented above) andapplying the calibration results to the microprocessor-based procedurethat estimates delays from impedance. Pacing therapy can then beadjusted to control the estimated delays within a safe or stable rangeabout a baseline.

Thus, various techniques are provided for estimating or predicting LAPfor use, e.g., in automatically adjusting pacing therapy and fordetecting and tracking heart failure. Individual implantable systems maybe equipped to perform some or all of these techniques. In someexamples, LAP is determined by combining estimates derived from thevarious individual techniques. Heart failure is then detected based onthe combined LAP estimate. Upon detecting of the onset of heart failure,appropriate warning signals may be generated for alerting the patient toconsult a physician. The warning signals can include “tickle” warningsignals applied to subcutaneous tissue and short range telemetry warningsignals transmitted to a warning device external to the patient such asa bedside monitor. The warning signals, as well as appropriatediagnostic information (such as the estimated LAP values), arepreferably forwarded to the physician by the bedside monitor. Variousother forms of therapy may also be automatically applied or modified bythe implanted system in response to heart failure, depending upon thecapabilities of the system. For example, if the device is equipped toperform CRT, then CRT pacing may be initiated or otherwise controlledbased on LAP. Also, if the implanted system is equipped with a drugpump, appropriate medications (such as diuretics) potentially may beadministered directly to the patient, depending upon the programming ofthe system. Alternatively, the estimated LAP may be presented directlyto the patient using a handheld or a bedside monitor, so that thepatients may utilize the estimated LAP reading to self-titrate oraldosages of heart failure medications based on a sliding scaleprescription that was provided to the patient in advance. This conceptis similar to the self-titration of insulin dosage based on a measuredblood sugar from a glucometer using a prescribed insulin sliding scale.

Although summarized with respect to estimating LAP based on LV-RVconduction delays, the techniques of the invention may be applied toestimating other parameters from the same or different conductiondelays. For example, LV end diastolic volume (EDV) or LV end diastolicpressure (EDP) may also be estimated, at least within some patients,based on LV-RV conduction delays by using appropriate calibrationfactors (e.g. Slope_(LV EDV/LV-RV), Baseline_(LV EVD/LV-RV) orSlope_(LV EDP/LV-RV), Baseline_(LV EVP/LV-RV)). As another example, LAPmay instead be estimated, within at least some patients, based on AVconduction delays by using appropriate calibration factors (e.g.Slope_(LAP/AV), P-wave morphology or width, Baseline_(LAP/AV)). As yetanother example, LAP may instead be estimated, within at least somepatients, based on intraventricular conduction delays by usingappropriate calibration factors (e.g. Slope_(LAP/LV1-LV2),Baseline_(LAP/V1-LV2)), particularly if the locations of the LV1 and LV2sensing/pacing locations are fairly widely separated within the LV.Thus, a variety of cardiac chamber parameters may be estimated based ona variety of cardiac electrical conduction delays. LAP is generallypreferred as it is strongly correlated with CHF. LV-RV conduction delaysare may be preferred as such delays provide perhaps the most effectivedelay for use in estimating LAP. However, in at least some patients,other conduction delays might instead be preferred for use in estimatingother cardiac performance parameters.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages of the invention may be more readilyunderstood by reference to the following description taken inconjunction with the accompanying drawings, in which:

FIG. 1 is a stylized representation of an exemplary implantable medicalsystem equipped with a conduction delay-based LAP estimation system;

FIG. 2 is a flow diagram providing a broad overview of conductiondelay-based cardiac pressure estimation techniques that may be performedby the system of FIG. 1;

FIG. 3 is a flow diagram summarizing an illustrative technique performedin accordance with the general technique of FIG. 2 wherein cardiacpressure is estimated from conduction delays using pre-determinedconversion factors and wherein pacing timing parameters are thenadaptively adjusted based on the estimated pressure values;

FIG. 4 is a graph illustrating a linear correlation between LAP andLV-RV delay that may be exploited by the estimation procedure of FIG. 3;

FIG. 5 is a flow diagram illustrating a particular example of theillustrative technique of FIG. 3 wherein LAP is estimated based onmeasured LV-RV delays, along with appropriate slope and baselinecalibration values, to produce a qLAP value;

FIG. 6 is a graph providing exemplary data illustrating changes overtime in qLAP values estimated within a canine test subject using thetechnique of FIG. 5;

FIG. 7 is a flow diagram illustrating a closed-loop procedure foradaptively adjusting pacing parameters based on estimated cardiacpressure values obtained in accordance with the exemplary estimationtechnique of FIG. 5;

FIG. 8 is a flow diagram illustrating an exemplary procedure forcalibrating the LV-RV delay-based LAP estimation technique of FIG. 5using calibration parameters obtained within the patient in which thesystem is implanted;

FIG. 9 is a graph illustrating a linear relationship between qLAP andLV-RV delay calibration values exploited by the calibration technique ofFIG. 8;

FIG. 10 is a flow diagram illustrating an exemplary procedure forre-calibrating the baseline value of the LV-RV delay-based LAPestimation technique of FIG. 5 using additional calibration parametersobtained within the patient while performing the Valsalva maneuver;

FIG. 11 is a flow diagram illustrating an exemplary procedure forre-calibrating both slope and baseline values of the LV-RV delay-basedLAP estimation technique of FIG. 5 using additional calibrationparameters obtained within the patient while performing the Valsalvamaneuver;

FIG. 12 is a graph illustrating a linear relationship between qLAP andLV-RV delay calibration values exploited by the re-calibration techniqueof FIG. 11, and, in particular, illustrating a zero LAP value obtainedwithin the patient during the Valsalva maneuver;

FIG. 13 is a flow diagram illustrating an exemplary procedure forcalibrating the LAP-based technique of FIG. 5 using calibrationparameters obtained from a population of test subjects;

FIG. 14 is a simplified, partly cutaway view, illustrating the pacer/ICDof FIG. 1 along with a more complete set of leads implanted in the heartof the patient;

FIG.15 a functional block diagram of the pacer/ICD of FIG. 14,illustrating basic circuit elements that provide cardioversion,defibrillation and/or pacing stimulation in the heart and particularlyillustrating components for estimating LAP based on conduction delaysand for adaptively adjusting pacing parameters in response thereto;

FIG. 16 is a functional block diagram illustrating components of adevice programmer of FIG. 15, and in particular illustrating aprogrammer-based LAP estimation calibration system;

FIG. 17 summarizes a technique for estimating conduction delays based onmeasured impedance values for use with the system of FIG. 1;

FIG. 18 illustrates a relationship between admittance (i.e. thereciprocal of impedance) and conduction time delays, which is exploitedby the technique of FIG. 17;

FIG. 19 illustrates changes on conduction time delays that areindicative of heart failure, which may also be exploited by thetechnique of FIG. 17; and

FIG. 20 provides a stylized representation of a heart and particularlyillustrates various impedance vectors that may be exploited used tomeasure impedance for use with the technique of FIG. 17.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following description includes the best mode presently contemplatedfor practicing the invention. The description is not to be taken in alimiting sense but is made merely for the purpose of describing thegeneral principles of the invention. The scope of the invention shouldbe ascertained with reference to the issued claims. In the descriptionof the invention that follows, like numerals or reference designatorswill be used to refer to like parts or elements throughout.

Overview of Implantable Medical System

FIG. 1 provides a stylized representation of an exemplary implantablepacing medical system 8 capable of detecting electrical conductiondelays within the heart of the patient and estimating LAP based on theconduction delays. To this end, implantable system 8 includes apacer/ICD 10 or other cardiac stimulation device that incorporatesinternal components (shown individually in FIG. 15, and discussed below)for detecting one or more conduction delays using electrodes mounted toa set of sensing/pacing leads 12 and for estimating LAP or other cardiacperformance parameters based on the conduction delays. In FIG. 1, onlytwo leads are shown. A more complete set of leads is illustrated in FIG.14, which is discussed below. Within many of the exemplaryimplementations described herein, LAP is estimated based on LV-RV delaysdetected by the pacer/ICD. However, other conduction delays can beexploited, alone or in combination, to estimate other cardiac pressurevalues or other cardiac performance parameters, such as EDV. LAP isemphasized as it is correlated with CHF. Predetermined conversionfactors stored within the pacer/ICD are used to convert the conductiondelays into LAP values or other appropriate cardiac chamber parameters.The conversion factors may be, for example, slope and baseline valuesderived during an initial calibration procedure performed by an externalsystem, such as an external programmer (FIG. 16.) As will be explained,the baseline value may be periodically re-calibrated by the pacer/ICDitself. The slope value is assumed to remain substantially unchangedsuch that re-calibration of the slope is typically not required.

FIG. 2 provides a broad summary of the cardiac pressure estimationtechniques that may be performed by the pacer/ICD of FIG. 1. At step 50,the pacer/ICD measures an electrical conduction delay in the heart ofthe patient where the delay is affected by cardiac pressure such as leftatrial pressure (LAP). At step 52, the pacer/ICD then estimates LAP orother suitable cardiac chamber values within the patient from theelectrical conduction delay. The pacer/ICD of FIG. 1 is also equipped totrack changes in the estimated LAP values so as to detect and track CHFand to adjust pacing parameters in an effort to mitigate CHF, such asCRT parameters. Techniques for performing CRT are discussed in thepatents to Mathis, et al., Kramer, et al., to Stahmann, et al., citedabove. Adaptively adjustment techniques set forth in the Panescu et al.patent application, “Closed-Loop Adaptive Adjustment of Pacing Therapybased on Cardiogenic Impedance Signals Detected by an ImplantableMedical Device,” cited above, may be exploited. Additionally oralternatively, the pacer/ICD may issue warning signals, if warranted.For example, if the estimated LAP exceeds a threshold indicative of CHF,warning signals may be generated to warn the patient, using either animplanted warning device 14 or an external bedside monitor/handheldwarning device 16. Internal warning device 14 may be a vibrating deviceor a “tickle” voltage device that, in either case, provides perceptiblestimulation to the patient to alert the patient so that the patient mayconsult a physician. In one example, once the tickle warning is felt,the patient positions an external warning device above his or her chest.The handheld device receives short-range telemetry signals from theimplanted device and provides audible or visual verification of thewarning signal. The handheld warning device thereby providesconfirmation of the warning to the patient along with a display of theestimated LAP, who may be otherwise uncertain as to the reason for theinternally generated warning signal. For further information regardingthis warning/notification technique, see U.S. patent application Ser.No. 11/043,612, of Kil et al., filed Jan. 25, 2005, entitled “System andMethod for Distinguishing among Ischemia, Hypoglycemia and Hyperglycemiausing an Implantable Medical Device.”

If a bedside monitor is provided, the bedside monitor provides audibleor visual alarm signals to alert the patient or caregiver, as well astextual or graphic displays. In addition, diagnostic informationpertaining to the deteriorating cardiac condition is transferred to thebedside monitor or is stored within the pacer/ICD for subsequenttransmission to an external programmer (not shown in FIG. 1) for reviewby a physician or other medical professional. The physician may thenprescribe any other appropriate therapies to address the condition. Thephysician may also adjust the operation of the pacer/ICD to activate,deactivate or otherwise control any therapies that are automaticallyapplied. The bedside monitor may be directly networked with acentralized computing system, such as the HouseCall™ system of St. JudeMedical, for immediately notifying the physician of any significantincrease in LAP. Networking techniques for use with implantable medicalsystems are set forth, for example, in U.S. Pat. No. 6,249,705 to Snell,entitled “Distributed Network System for Use with Implantable MedicalDevices”.

In addition to CRT, other forms of therapy may also be controlled by thepacer/ICD in response to changes in LAP. In this regard, if theimplanted system is equipped with a drug pump, appropriate medicationsmay be automatically administered upon detection of a significantincrease in LAP due to heart failure. For example, heart failuremedications may be delivered directly to the patient via the drug pump,when needed. Alternatively, if a drug pump is not available, the patientmay be provided with instructions depending on the estimated LAP as towhat dosage to take for various heart failure medications. Exemplaryheart failure medications include angiotensin-converting enzyme (ACE)inhibitors, diuretics, nitrates, digitalis and compounds such ascaptopril, enalapril, lisinopril and quinapril. For example, upondetection of a high LAP level, the dosage of diuretics could beincreased, either automatically via a drug pump or by sendingappropriate instructions to the bedside monitor for alerting the patientor caregiver. Depending upon the particular medication, alternativecompounds may be required for use in connection with an implantable drugpump. Routine experimentation may be employed to identify medicationsfor treatment of heart failure or other conditions that are safe andeffective for use in connection with an implantable drug pump. Dosagesmay be titrated based upon the severity of heart failure as determinedfrom LAP.

Various techniques may be employed to confirm the detection of heartfailure (or other medical conditions) made by the pacer/ICD based on theanalysis of the conduction delay before drug therapy is delivered.Exemplary impedance-based heart failure detection/evaluation techniquesare set forth in U.S. patent application Ser. No. 11/559,235, citedabove. See, also, U.S. Pat. No. 6,748,261, entitled “Implantable medicaldevice for and Method of Monitoring Progression or Regression of HeartDisease by Monitoring Interchamber Conduction Delays”; U.S. Pat. No.6,741,885, entitled “Implantable Cardiac Device for Managing theProgression of Heart Disease and Method”; U.S. Pat. No. 6,643,548,entitled “Implantable medical device for Monitoring Heart Sounds toDetect Progression and Regression of Heart Disease and Method Thereof”;U.S. Pat. No. 6,572,557, entitled “System and Method for MonitoringProgression of Cardiac Disease State using Physiologic Sensors”; andU.S. Pat. No. 6,480,733, entitled “Method for Monitoring Heart Failure”,each assigned to Pacesetter, Inc.

Hence, FIGS. 1 and 2 provide an overview of an implantable medicalsystem capable of estimating LAP based on conduction delays, adjustingpacing parameters, delivering any appropriate warning/notificationsignals, and selectively delivering medications, when warranted.Embodiments may be implemented that do not necessarily perform all ofthese functions. For example, embodiments may be implemented thatestimate LAP but do not automatically initiate or adjust therapy.Moreover, systems provided in accordance with the invention need notinclude all of the components shown in FIG. 1. In many cases, forexample, the system will include only a pacer/ICD and its leads.Implantable warning devices and drug pumps are not necessarilyimplanted. Some implementations may employ an external monitor fordisplaying warning signals without any internal warning device. Theseare just a few exemplary embodiments. No attempt is made herein todescribe all possible combinations of components that may be provided inaccordance with the general principles of the invention. In addition,note that the particular locations and sizes of the implanted componentsshown in FIG. 1 are merely illustrative and may not necessarilycorrespond to actual implant locations. Although internal signaltransmission lines provided are illustrated in FIG. 1 forinterconnecting the various implanted components, wireless signaltransmission may alternatively be employed.

Overview of Conduction Delay-Based Estimation Techniques

FIG. 3 provides an overview of LAP estimation techniques that may beperformed by the pacer/ICD of FIG. 1 or other implantable medicaldevice. At step 100, the pacer/ICD measures an electrical conductiondelay in the heart of the patient where the delay is affected by changesin chamber pressure, such as by measuring an interventricular LV-RVdelay for use in estimating LAP. An exemplary interventricularconduction path 101 along which the delay may be measured is shown inFIG. 14, which is described more fully below. The conduction pathextends through myocardial tissue between, in this particular example, apair of LV tip and ring electrodes 426 and 425 of a coronary sinus (CS)lead 424 and a paired of RV tip and ring electrodes 424 and 434 of an RVlead 430. The tip and ring electrodes 422, 423 of a RA lead 420 are alsoshown. The exemplary interventricular conduction path 101 extends, asshown, down from the LV electrodes toward the apex of the ventricles andthen in to the RV. Once the myocardium of the LV begins to depolarize inthe vicinity of the LV electrodes, electrical depolarization signalspropagate along the path ultimately triggering myocardial depolarizationwithin the RV, which is sensed using the RV electrodes. The time duringwhich the depolarization signal propagates along this (or other)interventricular paths is the conduction time delay measured at step 100of FIG. 3. It should be understood that the LV-RV delay may be negative,i.e. the RV may depolarize first, followed by the LV (with the RVdepolarizing either naturally or due to a V-pulse delivered to the RV.)That is, depolarization signals may propagate along an interventricularconduction path from the RV to LV, instead of vice versa. Herein, forclarity, when the LV-RV delay is negative, the delay is insteadtypically referred to as an RV-LV delay.

The inter-ventricular conduction time delay following the delivery of aleft ventricular pacing stimulus may be used to estimate LV size and/orLV filling pressure. At the time a pacing stimulus is delivered to theLV the chamber is filled with blood and corresponds to the LV EDV. Thepacing stimulus will cause the LV muscle to depolarize and subsequentlycontract. While the LV depolarization occurs the depolarizationwavefront travels across the LV toward the right ventricle andultimately causes the RV to depolarize and subsequently contract. Thedelay between the time when the LV pacing stimulus was administered andthe time when the RV depolarizes may be proportional to the LV EDV,which is also proportional to the LV EDP. LV EDP is a good estimate forLAP in the absence of significant mitral valve stenosis. Thus, theinterventricular time delay in cardiac depolarization and/or contractionfollowing a ventricular stimulus may be used, at least within somepatients, to estimate the end-diastolic ventricular filling volumeand/or filling pressure.

Moreover, the duration of the interventricular conduction delay dependslargely upon the distance over which the depolarization signaltraverses, which depends, in part, on the sizes of the chambers of theheart it passes through. As heart failure progress, pressure within theLV increases and the LV chamber often becomes distended, resulting in agenerally longer conduction time delay. Hence, there is, in at leastsome patients, a correlation between interventricular conduction timedelays and LV chamber size and LV chamber pressure. Hence, in suchpatients, there is a correlation between LV-RV delay and LV EDV and LVEDP. Likewise, as heart failure progresses, LAP increases. Accordingly,within at least some patients, there is also a correlation between LV-RVdelay and LAP. The techniques of the invention exploit this correlationto estimate LAP from the LV-RV delay. LV EDV and LV EDP may also beestimated from the LV-RV delay.

FIG. 4 illustrates data collected from a canine test subject showing thecorrelation between RV-LV delay (in msecs) and LAP (in mmHg). In thisexample, the RV-LV delay was measured based on paced RV pulses using theQuickOpt techniques, discussed below. LAP was measured using a HeartPODLAP detection device developed by Savacor Inc., now owned by St. JudeMedical. HeartPOD is a trademark of St. Jude Medical. The canine testsubject was paced via a rapid pacing protocol so as to induce andemulate heart failure, which resulted in increasing LAP values overtime. As can be seen, there is a linear correlation between LAP andRV-LV delay within this test subject, as represented by linearregression line 103. Similar correlations are present in at least some,and likely most, human heart failure patients. Based on the correlation,LAP can be estimated based on RV-LV conduction delays (or LV-RV delays),at least within patients where the correlation is present.

An LV-RV conduction delay may be measured, for example, by tracking thetime between when a V-pulse is delivered to the LV using the LV tip andring electrodes and the peak of a QRS-complex sensed within the RV usingthe RV tip and ring electrodes. An RV-LV conduction delay may bemeasured, for example, by tracking the time between when a V-pulse isdelivered to the RV using the RV tip and ring electrodes and the peak ofa QRS-complex sensed within the LV using the LV tip and ring electrodes.However, other points within the QRS-complexes might instead beemployed, such as the starting point of a complex. The peak is typicallythe easiest to detect. Also, instead of using the time at which aV-pulse is delivered, the pacer/ICD might instead detect and use thepeak of the resulting evoked response (RV). Hence, conduction delaysderived from paced events may be quantified in a variety of ways. Aswill be explained, conversion factors are used to convert the measuredtime delay into LAP or other cardiac performance values. So long as thesystem uses the appropriate conversion factors, the conduction delaysmay be measured using any suitable technique. Also, the pacer/ICD is notlimited to measuring conduction delays from paced events. As anotherexample, the conduction delay might instead be measured between the peakof a QRS-complex sensed in the LV using the tip and ring electrodes ofthe CS lead and the peak of the QRS-complex sensed within the RV, againusing tip and ring electrodes of a RV lead. Again, the conduction delaymay be quantified in a variety of ways, so long as the appropriateconversion factors are employed.

At step 102, the pacer/ICD inputs predetermined conversion factors forconverting the measured time delay to an estimate of cardiac chamberpressure, such as predetermined slope and baseline values obtained fromlinear regression analysis applied to data of the type shown in FIG. 4(though, of course, collected from human patients). Exemplarycalibration techniques for determining the conversion factors based on alinear equation derived from linear regression are discussed below. Atstep 104, the pacer/ICD then estimates LAP or other cardiac pressurevalues within the patient by applying the conversion factors retrievedfrom memory to the measured time delays or by using a neural network,linear discriminant analyzer (LDA) or other appropriate technique. Also,the pacer/ICD may classify the pressure value within discrete intervals,such as LOW, MEDIUM and HIGH. That is, the pacer/ICD need not calculatespecific values of the cardiac pressure but may instead simply determinewhether the pressure is low, medium or higher, or within otherpredetermined ranges. The discrete intervals may be used as part of aprediction model that predicts LAP trends in a discrete fashion.

When using slope and baseline conversion factors to estimate specificvalues of pressure, cardiac pressure may be generally estimated using:

Cardiac Pressure=Delay*Slope+Baseline

where Delay represents the measured conduction delay, i.e. LV-RV delay,etc., and Slope and Baseline represent the conversion factorsappropriate for use with the particular delay. This formula assumes alinear relationship between cardiac pressure and the measured conductiondelay, which is an appropriate presumption based on the particularconduction delays discussed herein, at least insofar as estimating LAPis concerned. Routine experimentation may be performed to determinewhether a linear relationship is also suitable for use in estimatingother particular cardiac chamber values, such as LVP, LV EDV or LV EDP,or is also suitable for use with other conduction delays, such as RA-LV,RA-RV, RA-LA, etc. Moreover, it should be understood that linear modelsneed not necessarily be used, i.e. more sophisticated correlation modelsmay instead by employed. Linear models are preferred in view of theirsimplicity. As noted, neural networks or LDAs may instead be employed,where appropriate.

At step 106, the pacer/ICD then adaptively adjusts pacing timingparameters in a closed loop to improve LAP or other cardiac performancevalues. For example, LV-RV delays or AV delays may be adjusted in aneffort to reduce LAP. That is, a combination of AV delay and LV-RV delayvalues are selected that yield the lowest LAP values. However, otherdelay parameters may be adjusted as well, such as inter-atrial delaysor, if the implantable system is equipped to pace at two or morelocations within a given atrial or ventricular chamber, thenintra-atrial or intraventricular delays may be adjusted. Adaptiveadjustment techniques are discussed in greater detail below. At step108, the pacer/ICD tracks CHF, controls pacing therapy (such as CRT),generates warnings and/or stores diagnostic information based onestimated LAP values or other estimated cardiac chamber parameters. Asalready explained, the warnings and/or diagnostic data can be forwardedto a physician for review. Preferably, the diagnostic data includes theestimated LAP values for physician review. This is particularlyadvantageous since physicians are typically more comfortable reviewingLAP information than raw conduction delay values.

Preferably, steps 100-108 are repeated for each heartbeat to trackchanges in LAP on a beat-by-beat basis, adjust pacing parameters, trackCHF, etc. That is, in some implementations, a near real-time LAP(t)function may be estimated so as to allow the pacer/ICD to trackbeat-to-beat changes in LAP. This allows the pacer/ICD to respondpromptly to changes within the heart of the patient. Also, thebeat-by-beat LAP estimates may be applied to a predictor or predictionmodel so as to predict changes in LAP so that therapy may be controlledin advance of unacceptably high LAP levels or so that warnings may begenerated in advance.

If the LV and RV are both being paced so that interventricularconduction delays are not readily measurable via IEGMS, the pacer/ICDmay be programmed to periodically suspend RV pacing (or LV pacing) so asto permit at least a few intrinsic ventricular depolarizations so thatthe conduction delays can be measured. Alternatively, the electricalconduction delay technique of the invention may be used in conjunctionwith impedance-based mechanical delay techniques, which can deriveestimates of LAP during those heartbeats when LV-RV conduction delaysare not readily measurable. See, for example, U.S. patent applicationSer. No. 11/558,194, by Panescu et al., cited above. In general, theconduction delay-based LAP estimation techniques of the invention can becombined with a variety of other LAP estimation techniques to derive afinal estimate of LAP. Still further impedance signals may be analyzedto determine the electrical conduction delays from which cardiacpressure may then be estimated using appropriate conversion factors. Inthis regard, it is known in the art that electrical impedance changesmay be indicative of changes in heart chamber dimensions. See, e.g.,U.S. Pat. No. 5,003,976 to Alt. Alt describes that analyzing theimpedance between two intracardiac electrodes may be used to determinechanges in cardiac chamber volumes. As already explained, changes inchamber volume also affect conduction delays, allowing impedance signalsto be used to detect conduction delays, particularly in circumstancewhere such delays cannot readily be determined from IEGMs.

Although the examples described herein are primarily directed toestimating LAP, other cardiac performance parameters may alternativelybe estimated, such as LV EDV, LV EDP, RVP, RAP, etc., by usingappropriate conversion factors in combination with appropriateconduction delays. Otherwise routine experimentation may be performed toidentify particular parameters detectable using the techniques of theinvention and the appropriate conduction delays and conversion factors.In some cases, a linear conversion may not be suitable and algorithmsthat are more sophisticated may be required to convert conduction delaysinto parameter estimates. In some cases, multiple conduction delays maybe required to properly estimate a particular parameter. That is,multiple conduction delays may be measured using different electrodes soas to permit the pacer/ICD to estimate chamber pressures and volumeswithin different chambers of the heart, assuming appropriate conversionvalues have been determined and calibrated. To this end, the implantedsystem may be equipped, e.g., with multiple electrodes per lead or withmultiple leads per chamber. Unipolar, bipolar or cross-chamber sensingsystems may be employed, where appropriate.

Turning now to FIGS. 5-13, various illustrative embodiments will bedescribed in greater detail.

Exemplary LAP Estimation Techniques

FIG. 5 provides an LV-RV delay-based LAP detection example whereinQuickOpt procedures for ascertaining the conduction delays. At step 200,the pacer/ICD measures the LV-RV delay (D_(LV-RV)) based on time delaybetween an LV-pulse and an RV QRS-complex or between a pair of LV and RVQRS-complexes using QuickOpt or other suitable delay detectiontechnique. The QuickOpt technique is discussed in U.S. PatentApplication No. 2005/0125041, cited above. For the sake of completeness,pertinent portions of the QuickOpt code are provided in the attachedappendix (Appendix A). The example of Appendix A primarily operates toset RV thresholds. However, the LV-RV delay may be obtained usinginformation generated by the code. That is, in the code, “ndx_lv” is thelocation of the LV QRS. “ndx_rv” is the location of the RV QRS. Hence,the LV-RV delay may be obtained by subtracting ndx_rv from ndx_lv (orvice versa).

At step 202, the pacer/ICD inputs the particular slope and baselinevalues (Slope_(LAP/LV-RV) and Baseline_(AP/LV-RV)) for converting thedelay value (D_(LV-RV)) into an estimate of LAP (denoted qLAP_(LV-RV)).The slope and baseline values (which also may be referred to as gain andoffset values) are predetermined conversion values that the pacer/ICDretrieves from memory. Calibration techniques for initially deriving theconversion values will be discussed below with reference to FIGS. 8-13.At step 204, the pacer/ICD estimates LAP by applying the slope andbaseline values to the delay value:

qLAP _(LV-RV) =D _(LV-RV)*Slope_(LAP/LV-RV)+Baseline_(LAP/LV-RV)

As indicated by step 206, the pacer/ICD repeats for each heartbeat totrack qLAP(t). The LV-RV subscript is applied to qLAP to indicate thatthis estimate is made based on LV-RV delays (rather than some otherconduction delay value.) The LAP/LV-RV subscript is applied to Slope andBaseline to indicate that these conversion factors are appropriate foruse in estimating LAP based on LV-RV delays (rather than some othercardiac chamber parameter estimated from some other conduction delayvalue.)

FIG. 6 illustrates qLAP_(LV-RV) values obtained within the same caninetest subject of FIG. 4 showing changes over time as heart failure isinduced. Light-shaded dots 207 are qLAP_(LV-RV) values calculated asdescribed herein. The darker-shaded dots 209 are actual LAP valuesmeasured using the HeartPOD system, discussed above, which includes anLAP sensor. As can be seen, the qLAP_(LV-RV) values correlate fairlywell with the HeartPOD values, verifying that the estimation iseffective. (The qLAP_(LV-RV) values are not necessarily identical to theactual LAP values since qLAP_(LV-RV) merely provides an estimate of LAPand not a precise value.) The graph also shows zLAP values (representedby way of the light-shaded curve 211), as well as a six point movingaverage of ZLAP (represented by way of the dark-shaded curve 213). TheZLAP values were obtained using the impedance-based LAP estimationdetection techniques set forth in U.S. patent application Ser. No.11/559,235, cited above. (More generally, the techniques describedtherein are “admittance-based.”) As can be seen, the zLAP estimatesdiverge from qLAP_(LV-RV) values and from the true LAP values during thefirst couple of weeks of data. This is due to healing in and around therecently implanted electrodes, which affects impedance measurements.Hence, one advantage of the conduction delay-based techniques describedherein (i.e. qLAP techniques) is that reliable estimates can be achievedeven during the first few weeks following lead implant. (Note that thefigure also provides the slope and baseline values used in calculatingZLAP (based on admittance) and qLAP_(LV-RV) (based on the LV-RVconduction delay).)

Returning to FIG. 5, at step 208, the pacer/ICD adjusts the timingdelays (such as the LV-RV and AV delays) in an effort reduceqLAP_(LV-RV) so as to mitigate CHF or other heart ailments. In thisregard, the various pacing timing parameters noted above may beadaptively adjusted. That is, typically, at least the AV and LV-RVtiming parameters are adjusted. Advantageously, the direction andmagnitude of the adjustment need not be known in advance. Rather, thepacer/ICD makes an incremental adjustment in one timing parameter in onedirection, then determines whether the adjustment improved qLAP_(LV-RV)or not. If an improvement is gained, the pacer/ICD makes an additionalincremental adjustment in that timing parameter in that same directionin an attempt to achieve still further improvement. If the adjustmenthas an adverse effect on qLAP_(LV-RV), the pacer/[CD makes anincremental adjustment in the same timing parameter but in the oppositedirection in an attempt to achieve an improvement in qLAP_(LV-RV). Themagnitudes of the adjustments are adaptively varied so as to furtheroptimize the parameter. If the initial adjustment had no effect, thepacer/ICD selects a different timing parameter to adjust. Once aparticular parameter is optimized, the pacer/ICD can select a differentparameter. For example, once AV delay has been optimized, the W pacingdelay may then be optimized. The range within which the parameters areautomatically adjusted can be restricted via device programming toensure that the parameters remain within acceptable bounds.

Care should be taken when optimizing or adapting pacing parameters whenthe parameter that is to be optimized is the parameter that is initiallymeasured and used to estimate qLAP. Such closed loop feedback techniquesare not precluded but it is often appropriate to restrict the rangethrough which the parameters are automatically adjusted or by providingother suitable feedback control techniques. For example, insofar asoptimizing or adapting VV delays based on qLAP values derived from LV-RVdelays are concerned, the VV delay may be adjusted from a qLAP valueestimated based on LV-RV delays by defining suitable adjustmentcriteria. This is generally equivalent to a closed loop system where thefeedback variable is optimized to a pre-established criterion (e.g. bykeeping qLAP to less than 25 mmHg.). This is discussed more fully below.Similarly, qLAP could be used to adjust pacing sites to reach apre-established estimated LAP goal.

FIG. 7 provides an exemplary closed-loop adjustment procedure whereinpacing parameters are adaptively adjusted so as to reduce a qLAP butonly under certain conditions. Beginning at step 215, the pacer/ICDdetects detect patient activity level, patient posture, blood oxygensaturation values (SO₂) and heart rate. Patient activity may be detectedusing an accelerometer or other physical activity sensor mounted withinthe pacer/ICD itself or positioned elsewhere within the patient.Depending upon the implementation, the physical activity sensor may beemployed in conjunction with an “activity variance” sensor, whichmonitors the activity sensor diurnally to detect the low variance in themeasurement corresponding to a rest state. For a complete description ofan activity variance sensor, see U.S. Pat. No. 5,476,483 to Bornzin etal., entitled “System and Method for Modulating the Base Rate duringSleep for a Rate-Responsive Cardiac Pacemaker.” Techniques for detectingpatient posture or changes in posture are set forth in U.S. patentapplication Ser. No. 10/329,233, of Koh et al., entitled “System andMethod for Determining Patient Posture Based On 3-D Trajectory Using anImplantable Medical Device”. Other techniques are set forth in U.S. Pat.No. 6,044,297 to Sheldon, et al. “Posture and Device Orientation andCalibration for Implantable Medical Devices.” Techniques for detectingSO₂ are described in U.S. Pat. No. 5,676,141 to Hollub, entitled“Electronic Processor for Pulse Oximeters.” Depending upon theparticular application, either arterial SO₂ (i.e. SaO₂), or venous SO₂(i.e. SvO₂), or both, may be detected and exploited. Heart rate may bederived from an IEGM.

At step 217, the pacer/ICD determines whether all of the following aretrue: (1) the patient is at rest and has been at rest for somepredetermined amount of time, based on patient activity; (2) the postureis supine; (3) SO₂ is within an acceptable predetermined rangeconsistent with patient rest; and (4) heart rate is within an acceptablepredetermined range consistent with rest (such as a heart rate below 80beats per minute (bpm)). If these conditions are met, the pacer/ICDproceeds to steps 219-223 to adaptively adjusting the pacing parameters.That is, at step 219, the pacer/ICD measures conduction delay values,such as LV-RV delays. At step 221, the pacer/ICD calculates qLAP fromthe measured delay using the techniques discussed above. At step 223,the pacer/ICD adaptively adjusts pacing parameters such as CRT timingparameters in an effort to maintain qLAP within a predeterminedacceptable range and also records the latest timing parameters and qLAPvalues for subsequent physician review. For example, the pacer/ICD maybe programmed to attempt to maintain qLAP within the range of 10-15mmHg. In one example, if qLAP is initially found to be within thatrange, no pacing parameter adjustments are made. However, if qLAP isfound to be in the range of 15-25 mmHg, then CRT parameter are adjustedin an attempt to reduce qLAP to within 10-15 mmHg. If qLAP is found toexceed 25 mmHg, then the pacer/ICD may be programmed to warning thepatient (and/or the appropriate medical personal) and/or to initiateappropriate therapy. For example, if a drug pump is provided, thepacer/ICD may control the drug pump to deliver diuretics or othermedications directed to reducing LAP (assuming such medications areavailable and have been found to be safe and effective for delivery viaan implantable drug pump.) If no drug pump is provided, the pacer/ICDmay relay instruction signals to the patient (and/or appropriate medicalpersonnel) to direct the patient to take suitable medications. In thismanner, medications directed to reducing LAP may be titrated.Alternatively, warnings may simply be generated that direct the patientto see his or her physician. The following summarizes one exemplaryimplementation of these strategies:

If qLAP in healthy range (e.g. 10 mmHg<qLAP<15 mmHg), continue normalpacing

If qLAP above healthy range (e.g. qLAP>15 mmHg), adaptively adjustpacing timing parameters (including, e.g., CRT parameters) in an effortto return qLAP to healthy range; record latest timing parameters andqLAP value for subsequent physician review

If qLAP is significantly above healthy range (e.g. qLAP>25 mmHg),generate warnings and/or instruct patient to take medications

If qLAP below healthy range, (e.g. qLAP, 10 mmHg), generate warnings oflow LAP

Still further, any CRT adjustments may be made based not only on qLAPbut on other parameters as well. For example, adjustments may be made soas to maintain qLAP within a given range while also maintaining certainIEGM morphological parameters (such as P-wave width) within a certainrange. As can be appreciated a wide range of feedback strategies andtechniques may be exploited.

Processing then returns to step 215 and, so long as the conditions ofstep 217 are still met, the pacer/ICD will continually and incrementallyadjust the pacing parameters using the adaptive procedure. This helpsensure that adjustments are made while the patient is in a particularresting state so that changes to qLAP due to factors other than thechanges in the pacing parameters (such as patient activity) will notadversely affect the adaptive procedure. By looking at just qLAP values,which can be calculated fairly quickly, the procedure can typically beperformed in near real-time. Once the patient becomes active again,further adaptive adjustments to pacing parameters are suspended untilthe patient is again at rest. Note that the list of patient statusconditions in step 217 is merely exemplary. In other examples, more orfewer conditions may be used. For example, in other implementations, thepatient need not necessarily be supine. Also, if the patient is subjectto AF, the acceptable heart rate range may be expanded or that conditioneliminated entirely so that frequent episodes of AF do not preventadaptive adjustment of the pacing parameters.

Various additional techniques and strategies for adaptively optimizingpacing parameters may be employed, where appropriate, to supplement orenhance the techniques described herein. Examples are set forth in U.S.patent application Ser. No. 11/231,081, filed Sep. 19, 2005, of Turcott,entitled “Rapid Optimization of Pacing Parameters”; U.S. patentapplication Ser. No. 11/199,619, filed Aug. 8, 2005, of Gill et al,entitled “AV Optimization Using Intracardiac Electrogram”; U.S. patentapplication Ser. No. 11/366,930, of Mulleretal., filed Mar. 1, 2006,entitled “System and Method for Determining Atrioventricular PacingDelay based on Atrial Repolarization”; U.S. patent application Ser. No.10/928,586, of Bruhns et al., entitled “System and Method forDetermining Optimal Atrioventricular Delay based on Intrinsic ConductionDelays”, filed Aug. 27, 2004; and U.S. Pat. No. 6,522,923 to Turcott,entitled “Methods, Systems and Devices for Optimizing Cardiac PacingParameters Using Evolutionary Algorithms.” See, also, the adaptiveadjustment techniques described in the above-cited patent application ofPanescu et al. (Ser. No. 11/558,194).

The locations of pacing sites may also be adaptively adjusted based onqLAP. In one particular example, the pacer/ICD is equipped with Nelectrodes in the RV, where N is an arbitrary number of electrodes. Thepacer/ICD calculates qLAP when unipolar pacing is performed using eachRV electrode, i.e. RV₁—case, RV₂—case, RV₃—case, etc. The pacer/ICD thenselects the particular RV electrode that achieves the lowest value ofqLAP for use in performing further pacing. Once optimal pacing sites arechosen, CRT timing parameters may be optimized using the techniquesabove for use with that particular pacing site. Similarly, the LV leadmay carry multiple CRT pacing electrodes. In a similar fashion, optimalpacing configurations can be selected from the electrodes on the LVlead. Yet similarly, combined RV and LV pacing configurations may beselected to reduce qLAR Alternatively, all these pacing electrodes canbe separately, or individually, distributed on endocardial, epicardialor within myocardial tissue. The electrodes can be carried on separateleads, on multiple leads or implanted individually. Note that, wheneverswitching between pacing electrodes, new conversion factors will need tobe applied/available. Accordingly, the pacer/ICD will need to havesufficient resources to store the many conversion factors and to keeptrack of which ones are well calibrated and which ones are inaccurate(or otherwise not useable).

Calibration Techniques

A variety of techniques may be used to initially determine andsubsequently adjust the conversion values (Slope_(LAP/LV-RV) andBaseline_(LAP/LV-RV)), i.e. to calibrate the delay-based estimationtechnique of FIG. 5. FIG. 8 summarizes a technique wherein calibrationis performed based on calibration values obtained within the particularpatient in which the pacer/ICD is implanted. That is, the conversionvalues are optimized for use with the particular patient. The procedureof FIG. 8 is performed by a physician during the implant procedure ofthe pacer/ICD while venous access is readily available and a Swan-Ganzcatheter can be easily inserted. The procedure in FIG. 8 may be repeatedor performed alternatively at a follow-up session after implantation ofthe pacer/ICD. At step 210, an external calibration system (such as theexternal programmer of FIG. 15) detects or inputs a first delaycalibration value (D_(LV-RV/1)) and a corresponding first LAPcalibration value (LAP₁) measured while the patient is at rest.Preferably, the delay value (D_(LV-RV/1)) is detected by the pacer/ICDitself using its leads and its internal detection circuitry, thentransmitted to the external system. Simultaneously, LAP₁ is detectedusing, e.g., a Swan-Ganz catheter to measure PCWP. The LAP value is alsorelayed to the external programmer.

At step 212, detects a second delay calibration value (D_(LV-RV/1)) anda corresponding second LAP calibration value (LAP₂) measured at a timewhen the patient is subject to a condition significantly affecting LAPso that LAP₂ differs substantially from LAP₁. For example, the physicianmay have the patient perform isometric muscle contractions, particularusing thoracic muscles, so as to change LAP within the patient.Alternatively, the physician may administer vasodilatation orvasoconstriction medications, so as to change LAP, or may temporarilyreprogram the pacer/ICD to perform rapid pacing, which also changes LAP.Still further, the physician may have the patient perform the Valsalvamaneuver, which reduces effective LAP secondary to reduced venousreturn, or may instead have the patient perform the handgrip maneuver,which tends to increase LAP. (The Valsalva maneuver occurs when apatient forcibly exhales for about 15 seconds against a fixed resistancewith a closed glottis while contracting the abdominal muscles. A suddentransient increase in intra-thoracic and intra-abdominal pressuresoccurs, which tends to empty the chambers of the heart of blood, suchthat within 1 to 2 seconds (phase I of the Valsalva maneuver) theeffective right atrial and right ventricular pressures drop to zero,while following 5 seconds (Late phase II) the effective left atrial andleft ventricular pressures tend to reach zero.) Again, the conductiondelay value is detected by the pacer/ICD itself then transmitted to theexternal system.

Thus, after step 212, the external system has obtained at least twopairs of calibration values (LAP₁, D_(LV-RV/1) and LAP₂, D_(LV-RV/2))where the LAP values differ substantially from one another. Since theLV-RV conduction delay varies due to changes in LV chamber volume thatcorrelate with changes in the LAP, the delay values likewise differ fromone another, permitting reliable calculation of the slope and baselinevalues.

At step 214, the external system calculates Slope_(LAP/LV-RV) using:

Slope_(LAP/LV-RV)=(LAP₂ −LAP ₁)/(D _(LV-RV2) −D _(LV-RV/1)).

At step 216, the external system calculates Baseline_(LAP/LV-RV) using:

Baseline_(LAP/LV-RV) =LAP ₁−Slope_(LAP/LV-RV/1) *D _(LV-RV/1)

These values are then transmitted to the pacer/ICD for storage thereinfor use in estimating LAP based on newly detected delay values using thetechnique of FIG. 5. Preferably, qLAP values provided by the pacer/ICDare compared with LAP values detected using the Swan-Ganz catheter toverify that the estimation system of the pacer/ICD has been properlycalibrated.

As noted, LV-RV conduction delays are not the only delays that might beused in estimating LAP or other cardiac pressure values. Hence, thefirst and second delay calibration values are also more generallyreferred to herein as D₁ and D₂. The external system calculates Slopeusing:

Slope=(Pressure₂−Pressure₁)/(D₂ −D ₁).

The external system calculates Baseline using:

Baseline=Pressure₁−Slope*D₁.

FIG. 9 illustrates an exemplary pair of calibration values 220, 222,along with exemplary slope 224 and baseline values 226 derived therefromusing the technique of FIG. 8. Although only two pairs of calibrationvalues are used in the example of FIG. 8, it should be understood thatadditional pairs of calibration values might be obtained. Linearregression techniques may be used to derive slope and baseline valuesfrom a plurality of pairs of calibration values. Also, as indicated bystep 218, the recalibration procedure of FIG. 8 can be repeatedperiodically (such as during subsequent follow-up sessions with thepatient) to update both the slope and baselines values to respond tochanges, if any, that may arise within the patient, perhaps due toscarring near the sensing electrodes. Alternatively, a re-calibrationtechnique may be performed by the pacer/ICD itself that re-calibratesonly the baseline value. This is summarized in FIG. 10.

FIG. 10 illustrates a recalibration procedure performed by the pacer/ICDto re-calibrate the baseline value. The procedure exploits theassumption that the slope value, once calculated for a particularpatient, typically does not change significantly within the patient.This allows the baseline value to be re-calibrated independently of theslope value. At step 228, the pacer/ICD detects an additional delaycalibration value (D_(LV-RV/N)) while the patient performs the Valsalvamaneuver. As already explained, during the Valsalva maneuver effectiveLAP drops to zero or near zero. Hence, a separate measurement ofeffective LAP is not required. Under the assumption that effective LAPdrops to zero at the time when the additional delay value (D_(LV-RV/N))is measured, the baseline value can be re-calculated, at step 230, basedon the previous slope and the new delay value (D_(LV-RV/N)) using:

New_Baseline_(LAP/LV-RV)=−Slope_(LAP/LV-RV) *D _(LV-RV/N).

A particularly attractive feature of this recalibration procedure isthat it is non-invasive and can be performed in the ambulatory settingin the physician's office during a routine follow-up visit. Preferably,re-calibration is performed while the patient is clinically stable.

In some patients with diastolic heart failure and poor left ventricularcompliance who may have higher cardiac filling pressures (PCWP >20 mmHg)even when well compensated, the effective LAP may not drop completely tozero during a Valsalva maneuver and a correction term may need to beapplied to account for this possibility. (See, for example, FIG. 5 ofU.S. Patent Application 2004/0019285 of Eigler, et al., entitled“Apparatus for Minimally Invasive Calibration of Implanted PressureTransducers,” which is incorporated by reference herein in itsentirety.)

In order to determine whether a particular patient requires such acorrection term, a third measurement of the conduction delay (D₃) duringthe original calibration procedure FIG. 8 should be obtained while thepatient is performing the Valsalva maneuver. This assumes that D₁ and D₂were not obtained during a Valsalva maneuver. The correction term(qLAP_(VALSALVA)) is simply computed using:

qLAP _(VALSALVA) =D ₃*Slope_(LAP/LV-RV)+Baseline_(LAP/LV-RV)

wherein qLAP_(VALSALVA) is an effective LAP pressure value. Ideally, ifthe blood volume inside the left atrium significantly decreases duringthe Valsalva maneuver, then qLAP_(VALSALVA) will be near zero. Step 230may alternatively be computed using:

New_Baseline_(LAP/LV-RV) =qLAP _(VALSALVA) −Slope _(LAP/LV-RV) *D _(N).

The response of intracardiac pressures to the Valsalva is discussed inMcClean et al., “Noninvasive calibration of cardiac pressure transducersin patients with heart failure: An aid to implantable hemodynamicmonitoring and therapeutic guidance”, Journal of Cardiac Failure, Vol.12 No. 7 2006, pp 568-576. It is described therein that during theValsalva maneuver the effective PCWP reduces nearly to zero as describedabove. A similar observation was observed for other chambers of theheart. In particular, the effective residual pressure within a specificcardiac chamber (P_(eff)) was computed as the difference between themeasured intracardiac pressure (P_(intracardiac)) and the simultaneousintrathoracic or airway pressure (P_(airway)) averaged over the timeinterval from 5 to 10 seconds after the initiation of the Valsalvamaneuver (Late phase II). The effective intracardiac pressure (P_(eff))is computed using:

P _(eff) =P _(intracardiac) −P _(airway)

where (P_(airway)) is detected, e.g., using an external pressuredetection system. See, for example, the upper airway apparatus of FIG. 2of U.S. Patent Application 2004/0019285 of Eigler, et al., cited above.Thus, in order to estimate the effective LAP (LAP_(eff)) during theValsalva maneuver one may obtain this measurement directly by computingaverage of the difference between the PCWP and the simultaneous airwaypressure over the interval from 5 to 10 seconds following the initiationof the Valsalva maneuver (late Phase II). This may be written morespecifically as:

LAP _(eff) =PCWP−P _(airway)

and LAP_(eff) may be used alternatively as the correction term describedabove.

The new baseline value is then used when converting additionalconduction delay values to effective qLAP values (step 204 of FIG. 5.)As indicated by step 232, the pacer/ICD can periodically recalibrate itsestimation system by repeating the procedure to calculate newBaseline_(LAP/LV-RV) values while assuming Slope_(LAP/LV-RV) remainssubstantially constant and using the correction term where appropriate.

In practice, the procedure of FIG. 10 may be initiated by periodicallyhaving the pacer/ICD transmit a signal to the bedside monitor providinginstructions to the patient to perform the Valsalva maneuver. Thepacer/ICD detects the new conduction delay value during the Valsalvamaneuver and updates the baseline value. The pacer/ICD may beadditionally programmed to verify that the patient actually performedthe maneuver by, e.g., analyzing changes in respiration (as detectedusing otherwise conventional respiration detection techniques) to verifythat respiratory patterns consistent with the Valsalva maneuver occur.The pacer/ICD can also time its detection of the additional conductiondelay value based on the respiratory signals to help ensure that the newconduction delay value is measured at a point when effective LAP isexpected to be zero. Alternatively, the re-calibration technique may beperformed only under the supervision of a physician or other clinicianduring a follow-up session with the patient. Still, the re-calibrationprocedure eliminates the need to directly measure effective LAP duringthe follow-up using a Swan-Ganz catheter. The catheter is only employedduring the original calibration procedure. Thus, FIG. 10 illustrates atechnique wherein the baseline value is re-calibrated by the pacer/ICDunder the assumption that slope does not change by exploiting theValsalva maneuver. The Valsalva maneuver may also be exploited tore-calibrate both slope and baseline, if needed within a particularpatient. This is illustrated in FIGS. 11 and 12.

FIG. 11 summarizes a recalibration procedure performed by the pacer/ICDto re-calibrate both the slope and baseline values. The procedure can beused in patients where the slope value changes. At step 234, thepacer/ICD inputs the original conduction delay calibration value(D_(LV-RV/1)) and effective pressure calibration value (LAP₁) originallymeasured following device implant (FIG. 8) or during a previouscalibration procedure. The assumption is that LAP₁ is unchanged from theprevious calibration procedure. At step 236, the pacer/ICD detects anadditional conduction delay calibration value (D_(LV-RV/N)) while thepatient performs the Valsalva maneuver. As already noted, during theValsalva maneuver effective LAP typically drops to at or near zero andso separate measurement of effective LAP is not required. Rather, it isassumed that effective LAP is zero when the additional conduction delayvalue (D_(LV-RV/N)) is measured, thus allowing the slope to bere-calculated, at step 238, using:

New_Slope_(LAP/LV-RV) =−LAP ₁/(D _(LV-RV/N) −D _(LV-RV/1)).

Once the new slope value is calculated, the new baseline value can becalculated, at step 240, using:

New_Baseline_(LAP/LV-RV)=−New₁₃ Slope_(LAP/LV-RV) *D _(LV-RV/N).

More generally:

Slope=−Pressure₁/(D _(N) −D ₁) and

Baseline=−Slope*D _(N).

The new slope and baseline values are then used when convertingadditional conduction delay values to effective qLAP values (step 206 ofFIG. 5.) As indicated by step 242, the pacer/ICD can periodicallyrecalibrate its estimation system by repeating the procedure tocalculate new Baseline_(LAP/LV-RV) and Slope_(LAP/LV-RV) values andusing the correction term where appropriate. As with the procedure ofFIG. 10, the procedure of FIG. 11 may be initiated by periodicallyhaving the pacer/ICD transmit a signal to the bedside monitor providinginstructions to the patient to perform the Valsalva maneuver or theprocedure may be performed under the supervision of a physician or otherclinician.

FIG. 12 illustrates an exemplary pair of calibration values 244, 246,along with exemplary slope 248 and baseline values 250 derived therefromusing the technique of FIG. 11. The first pair of calibration values 244is obtained following implant. The second pair of calibration values 246is obtained during the re-calibration procedure while the patientperforms the Valsalva maneuver. Since the Valsalva maneuver is beingperformed, the effective LAP value of the second pair of calibrationvalues 246 is zero and so the pressure need not be measured. Theconduction delay value of the second pair along with the pressure andconduction delay values of the first pair are used to calculate the newslope 244 and baseline values 250 using the equations of FIG. 11.

Turning now to FIG. 13, techniques are summarized for calibrating orre-calibrating the conduction delay-based estimation procedure based ondata from a population of human patients or human test subjects. In thespecific example of FIG. 13, data is obtained from a plurality of testpatients subject to various stages of heart failure and have various LAPvalues. Beginning at step 252, the external calibration system detectsor inputs a plurality of conduction delay calibration values(D_(LV-RV/1-N)) and corresponding LAP calibration values (LAP_(1-N))within N different human test subjects equipped with pacer/ICDs, somehealthy, others suffering differing stages of heart failure, i.e.differing levels of severity of heart failure. The conduction delayvalues are detected by the pacer/[CDs of the test subjects, then relayedto the external calibration system. The LAP values may be obtained usingSwan-Ganz catheters or the like. Since the test subjects exhibitdiffering stages of heart failure, differing values of LAP are therebyexhibited. At step 254, the external system then calculatesSlope_(LAP/LV-RV) and Baseline_(LAP/LV-RV) values using linearregression based on the conduction delay calibration values(D_(LV-RV/1-N)) and the LAP calibration values (LAP_(1-N)). At step 256,the external system then stores the Slope_(LAP/LV-RV) andBaseline_(LAP/LV-RV) values within individual pacer/ICDs of individualpatients for use therein. By obtaining data from a population of testsubjects, the slope and baseline values are therefore likely to beeffective within a wide range of patients. In some patients, thesevalues may be sufficient to provide an adequate estimate of LAP. Inother patients, these values may be used as starting points for furtherre-calibration. For example, the slope value obtained via the techniqueof FIG. 13 may be used within a wide range of patients along withpatient-specific baseline values obtained using the baseline-onlyre-calibration procedure of FIG. 10.

Thus, a variety of techniques for calibrating the procedure, estimatingLAP and then tracking heart failure are provided. These may besupplemented by using other non-conduction delay-based cardiac pressuredetection and heart failure detection techniques. In someimplementations, before an alarm is activated or any therapy isautomatically delivered, the pacer/ICD employs at least one otherdetection technique to corroborate the detection of heart failure.Techniques for detecting or tracking heart failure are set forth thefollowing patents and patent applications: U.S. Pat. No. 6,328,699 toEigler, et al., entitled “Permanently Implantable System and Method forDetecting, Diagnosing and Treating Congestive Heart Failure”; U.S. Pat.No. 6,970,742 to Mann, et al., entitled “Method for Detecting,Diagnosing, and Treating Cardiovascular Disease”; U.S. Pat. No.7,115,095 to Eigler, et al., entitled “Systems and Methods forDetecting, Diagnosing and Treating Congestive Heart Failure”; U.S.patent application Ser. No. 11/100,008, of Kil et al., entitled “SystemAnd Method For Detecting Heart Failure And Pulmonary Edema Based OnVentricular End-Diastolic Pressure Using An Implantable Medical Device”,filed Apr. 5, 2005; U.S. patent application Ser. No. 11/014,276, of Minet al., entitled “System And Method For Predicting Heart Failure BasedOn Ventricular End-Diastolic Volume/Pressure Using An ImplantableMedical Device”, filed Dec. 15, 2004; U.S. patent application Ser. No.10/810,437, of Bornzin et al., entitled “System and Method forEvaluating Heart Failure Based on Ventricular End-Diastolic Volume Usingan Implantable Medical Device,” filed Mar. 26, 2004 and U.S. patentapplication Ser. No. 10/346,809, of Min et al., entitled “System andMethod for Monitoring Cardiac Function via Cardiac Sounds Using anImplantable Cardiac Stimulation Device,” filed Jan. 17, 2003. See also:U.S. Pat. No. 6,572,557, to Tchou, et al., cited above. U.S. Pat. No.6,645,153, to Kroll et al., entitled “System and Method for EvaluatingRisk of Mortality Due To Congestive Heart Failure Using PhysiologicSensors”, and U.S. Pat. No. 6,438,408 to Mulligan et al., entitled“Implantable Medical Device For Monitoring Congestive Heart Failure.”Also, other calibration procedures may potentially be exploited inconnection with the calibration techniques described herein. See, forexample, U.S. Patent Application 2004/0019285 of Eigler, et al., citedabove, particularly the various linear regression techniques discussedtherein. Also, see the calibration procedures set forth in: U.S. patentapplication Ser. No. 11/559,235, by Panescu et al., entitled “System andMethod for Estimating Cardiac Pressure Using Parameters Derived fromImpedance Signals Detected by an Implantable Medical Device,” citedabove.

The examples above primarily pertain to estimating LV-RV delays.However, as already noted, other conduction delays can be used toestimate LAP. In general, any conduction delay that is affected by aparticular cardiac pressure parameter might be exploited to estimatethat cardiac pressure parameter. For example, LAP may also be estimatedfrom AV delays. AV may be determined in much the same manner as LV-RVdelays are determined (i.e. paced on pacer or sensed atrial andventricular events.) Also, the morphology of the P-wave may be exploitedto estimate AV delays (such as its shape or width). Typically, the widerthe P-wave, the longer the AV delay. The narrower the P-wave, theshorter the AV delay. The morphology of atrial evoked responses may alsobe exploited to estimate AV delay. The QuickOpt code of the appendix maybe modified as needed to provide these parameters. The following is alist of parameters that generally can be exploited to estimate LAP orother cardiac pressure parameter and which can be obtained from theQuickOpt code of the appendix or from modified versions thereof:

A sense and A pace wave duration (indicates LA dilation and qLAP)

V sense: RV-LV conduction delay

RV pace-LV pace delay; LV-RV pace delay; or differences therebetween,including any appropriate correction terms.

PR and AR: atrio-ventricular delays.

RV-LV pace delay minus pacing latency (which is an alternative to Vsense that tests for heart block in patients.)

Although primarily described with respect to examples having apacer/ICD, other implantable medical devices may be equipped to exploitthe techniques described herein. For the sake of completeness, anexemplary pacer/ICD will now be described, which includes components forperforming the functions and steps already described. Also, an exemplaryexternal programmer will be described, which includes components forperforming the calibration steps already described.

Exemplary Pacer/ICD

With reference to FIGS. 14 and 15, a description of an exemplarypacer/ICD will now be provided. FIG. 14 provides a simplified blockdiagram of the pacer/ICD, which is a dual-chamber stimulation devicecapable of treating both fast and slow arrhythmias with stimulationtherapy, including cardioversion, defibrillation, and pacingstimulation, and also capable of estimating LAP or other forms ofcardiac pressure using impedance signals. To provide other atrialchamber pacing stimulation and sensing, pacer/ICD 10 is shown inelectrical communication with a heart 312 by way of a left atrial lead320 having an atrial tip electrode 322 and an atrial ring electrode 323implanted in the atrial appendage. Pacer/ICD 10 is also in electricalcommunication with the heart by way of a right ventricular lead 330having, in this embodiment, a ventricular tip electrode 332, a rightventricular ring electrode 334, a right ventricular (RV) coil electrode336, and a superior vena cava (SVC) coil electrode 338. Typically, theright ventricular lead 330 is transvenously inserted into the heart soas to place the RV coil electrode 336 in the right ventricular apex, andthe SVC coil electrode 338 in the superior vena cava. Accordingly, theright ventricular lead is capable of receiving cardiac signals, anddelivering stimulation in the form of pacing and shock therapy to theright ventricle.

To sense left atrial and ventricular cardiac signals and to provide leftchamber pacing therapy, pacer/ICD 10 is coupled to a CS lead 324designed for placement in the “CS region” via the CS os for positioninga distal electrode adjacent to the left ventricle and/or additionalelectrode(s) adjacent to the left atrium. As used herein, the phrase “CSregion” refers to the venous vasculature of the left ventricle,including any portion of the CS, great cardiac vein, left marginal vein,left posterior ventricular vein, middle cardiac vein, and/or smallcardiac vein or any other cardiac vein accessible by the CS.Accordingly, an exemplary CS lead 324 is designed to receive atrial andventricular cardiac signals and to deliver left ventricular pacingtherapy using at least a left ventricular tip electrode 326 and a LVring electrode 325, left atrial pacing therapy using at least a leftatrial ring electrode 327, and shocking therapy using at least a leftatrial coil electrode 328. With this configuration, biventricular pacingcan be performed. Although only three leads are shown in FIG. 14, itshould also be understood that additional leads (with one or morepacing, sensing and/or shocking electrodes) might be used and/oradditional electrodes might be provided on the leads already shown. Aninterventricular conduction delay 101, already discussed, is also shownin FIG. 14.

A simplified block diagram of internal components of pacer/ICD 10 isshown in FIG. 15. While a particular pacer/ICD is shown, this is forillustration purposes only, and one of skill in the art could readilyduplicate, eliminate or disable the appropriate circuitry in any desiredcombination to provide a device capable of treating the appropriatechamber(s) with cardioversion, defibrillation and pacing stimulation.The housing 340 for pacer/ICD 10, shown schematically in FIG. 15, isoften referred to as the “can”, “case” or “case electrode” and may beprogrammably selected to act as the return electrode for all “unipolar”modes. The housing 340 may further be used as a return electrode aloneor in combination with one or more of the coil electrodes, 328, 336 and338, for shocking purposes. The housing 340 further includes a connector(not shown) having a plurality of terminals, 342, 343, 344, 345, 346,348, 352, 354, 356 and 358 (shown schematically and, for convenience,the names of the electrodes to which they are connected are shown nextto the terminals). As such, to achieve right atrial sensing and pacing,the connector includes at least a right atrial tip terminal (A_(R) TIP)342 adapted for connection to the atrial tip electrode 322 and a rightatrial ring (A_(R) RING) electrode 343 adapted for connection to rightatrial ring electrode 323. To achieve left chamber sensing, pacing andshocking, the connector includes at least a left ventricular tipterminal (V_(L) TIP) 344, a left ventricular ring terminal (V_(L) RING)345, a left atrial ring terminal (A_(L) RING) 346, and a left atrialshocking terminal (A_(L) COIL) 348, which are adapted for connection tothe left ventricular ring electrode 326, the left atrial ring electrode327, and the left atrial coil electrode 328, respectively. To supportright chamber sensing, pacing and shocking, the connector furtherincludes a right ventricular tip terminal (V_(R) TIP) 352, a rightventricular ring terminal (V_(R) RING) 354, a right ventricular shockingterminal (V_(R) COIL) 356, and an SVC shocking terminal (SVC COIL) 358,which are adapted for connection to the right ventricular tip electrode332, right ventricular ring electrode 334, the V_(R) coil electrode 336,and the SVC coil electrode 338, respectively.

At the core of pacer/ICD 10 is a programmable microcontroller 360, whichcontrols the various modes of stimulation therapy. As is well known inthe art, the microcontroller 360 (also referred to herein as a controlunit) typically includes a microprocessor, or equivalent controlcircuitry, designed specifically for controlling the delivery ofstimulation therapy and may further include RAM or ROM memory, logic andtiming circuitry, state machine circuitry, and I/O circuitry. Typically,the microcontroller 360 includes the ability to process or monitor inputsignals (data) as controlled by a program code stored in a designatedblock of memory. The details of the design and operation of themicrocontroller 360 are not critical to the invention. Rather, anysuitable microcontroller 360 may be used that carries out the functionsdescribed herein. The use of microprocessor-based control circuits forperforming timing and data analysis functions are well known in the art.

As shown in FIG. 15, an atrial pulse generator 370 and a ventricularpulse generator 372 generate pacing stimulation pulses for delivery bythe right atrial lead 320, the right ventricular lead 330, and/or the CSlead 324 via an electrode configuration switch 374. It is understoodthat in order to provide stimulation therapy in each of the fourchambers of the heart, the atrial and ventricular pulse generators, 370and 372, may include dedicated, independent pulse generators,multiplexed pulse generators or shared pulse generators. The pulsegenerators, 370 and 372, are controlled by the microcontroller 360 viaappropriate control signals, 376 and 378, respectively, to trigger orinhibit the stimulation pulses.

The microcontroller 360 further includes timing control circuitry (notseparately shown) used to control the timing of such stimulation pulses(e.g., pacing rate, AV delay, atrial interconduction (inter-atrial)delay, or ventricular interconduction (V-V) delay, etc.) as well as tokeep track of the timing of refractory periods, blanking intervals,noise detection windows, evoked response windows, alert intervals,marker channel timing, etc., which is well known in the art. Switch 374includes a plurality of switches for connecting the desired electrodesto the appropriate I/O circuits, thereby providing complete electrodeprogrammability. Accordingly, the switch 374, in response to a controlsignal 380 from the microcontroller 360, determines the polarity of thestimulation pulses (e.g., unipolar, bipolar, combipolar, etc.) byselectively closing the appropriate combination of switches (not shown)as is known in the art.

Atrial sensing circuits 382 and ventricular sensing circuits 384 mayalso be selectively coupled to the right atrial lead 320, CS lead 324,and the right ventricular lead 330, through the switch 374 for detectingthe presence of cardiac activity in each of the four chambers of theheart. Accordingly, the atrial (ATR. SENSE) and ventricular (VTR. SENSE)sensing circuits, 382 and 384, may include dedicated sense amplifiers,multiplexed amplifiers or shared amplifiers. The switch 374 determinesthe “sensing polarity” of the cardiac signal by selectively closing theappropriate switches, as is also known in the art. In this way, theclinician may program the sensing polarity independent of thestimulation polarity. Each sensing circuit, 382 and 384, preferablyemploys one or more low power, precision amplifiers with programmablegain and/or automatic gain control, bandpass filtering, and a thresholddetection circuit, as known in the art, to selectively sense the cardiacsignal of interest. The automatic gain control enables pacer/[CD 10 todeal effectively with the difficult problem of sensing the low amplitudesignal characteristics of atrial or ventricular fibrillation. Theoutputs of the atrial and ventricular sensing circuits, 382 and 384, areconnected to the microcontroller 360 which, in turn, are able to triggeror inhibit the atrial and ventricular pulse generators, 370 and 372,respectively, in a demand fashion in response to the absence or presenceof cardiac activity in the appropriate chambers of the heart.

For arrhythmia detection, pacer/ICD 10 utilizes the atrial andventricular sensing circuits, 382 and 384, to sense cardiac signals todetermine whether a rhythm is physiologic or pathologic. As used herein“sensing” is reserved for the noting of an electrical signal, and“detection” is the processing of these sensed signals and noting thepresence of an arrhythmia. The timing intervals between sensed events(e.g., AS, VS, and depolarization signals associated with fibrillationwhich are sometimes referred to as “F-waves” or “Fib-waves”) are thenclassified by the microcontroller 360 by comparing them to a predefinedrate zone limit (i.e., bradycardia, normal, atrial tachycardia, atrialfibrillation, low rate VT, high rate VT, and fibrillation rate zones)and various other characteristics (e.g., sudden onset, stability,physiologic sensors, and morphology, etc.) in order to determine thetype of remedial therapy that is needed (e.g., bradycardia pacing,antitachycardia pacing, cardioversion shocks or defibrillation shocks).

Cardiac signals are also applied to the inputs of an analog-to-digital(A/D) data acquisition system 390. The data acquisition system 390 isconfigured to acquire intracardiac electrogram signals, convert the rawanalog data into a digital signal, and store the digital signals forlater processing and/or telemetric transmission to an external device402. The data acquisition system 390 is coupled to the right atrial lead320, the CS lead 324, and the right ventricular lead 330 through theswitch 374 to sample cardiac signals across any pair of desiredelectrodes. The microcontroller 360 is further coupled to a memory 394by a suitable data/address bus 396, wherein the programmable operatingparameters used by the microcontroller 360 are stored and modified, asrequired, in order to customize the operation of pacer/ICD 10 to suitthe needs of a particular patient. Such operating parameters define, forexample, the amplitude or magnitude, pulse duration, electrode polarity,for both pacing pulses and impedance detection pulses as well as pacingrate, sensitivity, arrhythmia detection criteria, and the amplitude,waveshape and vector of each shocking pulse to be delivered to thepatient's heart within each respective tier of therapy. Other pacingparameters include base rate, rest rate and circadian base rate.

Advantageously, the operating parameters of the implantable pacer/ICD 10may be non-invasively programmed into the memory 394 through a telemetrycircuit 400 in telemetric communication with the external device 402,such as a programmer, transtelephonic transceiver or a diagnostic systemanalyzer. The telemetry circuit 400 is activated by the microcontrollerby a control signal 406. The telemetry circuit 400 advantageously allowsintracardiac electrograms and status information relating to theoperation of pacer/ICD 10 (as contained in the microcontroller 360 ormemory 394) to be sent to the external device 402 through an establishedcommunication link 404. Pacer/ICD 10 further includes an accelerometeror other physiologic sensor 408, commonly referred to as a“rate-responsive” sensor because it is typically used to adjust pacingstimulation rate according to the exercise state of the patient.However, the physiological sensor 408 may further be used to detectchanges in cardiac output, changes in the physiological condition of theheart, or diurnal changes in activity (e.g., detecting sleep and wakestates) and to detect arousal from sleep. Accordingly, themicrocontroller 360 responds by adjusting the various pacing parameters(such as rate, AV delay, V-V delay, etc.) at which the atrial andventricular pulse generators, 370 and 372, generate stimulation pulses.While shown as being included within pacer/ICD 10, it is to beunderstood that the physiologic sensor 408 may also be external topacer/ICD 10, yet still be implanted within or carried by the patient. Acommon type of rate responsive sensor is an activity sensorincorporating an accelerometer or a piezoelectric crystal, which ismounted within the housing 340 of pacer/ICD 10. Other types ofphysiologic sensors are also known, for example, sensors that sense theoxygen content of blood, respiration rate and/or minute ventilation, pHof blood, ventricular gradient, etc.

The pacer/ICD additionally includes a battery 410, which providesoperating power to all of the circuits shown in FIG. 15. The battery 410may vary depending on the capabilities of pacer/ICD 10. If the systemonly provides low voltage therapy, a lithium iodine or lithium copperfluoride cell typically may be utilized. For pacer/ICD 10, which employsshocking therapy, the battery 410 should be capable of operating at lowcurrent drains for long periods, and then be capable of providinghigh-current pulses (for capacitor charging) when the patient requires ashock pulse. The battery 410 should also have a predictable dischargecharacteristic so that elective replacement time can be detected.Accordingly, appropriate batteries are employed.

As further shown in FIG. 15, pacer/ICD 10 is shown as having animpedance measuring circuit 412, which is enabled by the microcontroller360 via a control signal 414. Uses for an impedance measuring circuitinclude, but are not limited to, lead impedance surveillance during theacute and chronic phases for proper lead positioning or dislodgement;detecting operable electrodes and automatically switching to an operablepair if dislodgement occurs; measuring respiration or minuteventilation; measuring thoracic impedance for determining shockthresholds; detecting when the device has been implanted; measuringrespiration; and detecting the opening of heart valves, etc. Theimpedance measuring circuit 412 is advantageously coupled to the switch474 so that any desired electrode may be used. The impedance measuringcircuit 412 also detects the impedance signals discussed above if ZLAPis to be estimated, in addition to qLAP. That is, impedance measuringcircuit 412 is an electrical impedance (Z) detector operative to detectan electrical impedance (Z) signal within the patient along at least onesensing vector wherein impedance is affected by cardiac pressure.

In the case where pacer/ICD 10 is intended to operate as an implantablecardioverter/defibrillator (ICD) device, it detects the occurrence of anarrhythmia, and automatically applies an appropriate electrical shocktherapy to the heart aimed at terminating the detected arrhythmia. Tothis end, the microcontroller 360 further controls a shocking circuit416 by way of a control signal 418. The shocking circuit 416 generatesshocking pulses of low (up to 0.5 joules), moderate (0.5-10 joules) orhigh energy (11 to 40 joules), as controlled by the microcontroller 360.Such shocking pulses are applied to the heart of the patient through atleast two shocking electrodes, and as shown in this embodiment, selectedfrom the left atrial coil electrode 328, the RV coil electrode 336,and/or the SVC coil electrode 338. The housing 340 may act as an activeelectrode in combination with the RV electrode 336, or as part of asplit electrical vector using the SVC coil electrode 338 or the leftatrial coil electrode 328 (i.e., using the RV electrode as a commonelectrode). Cardioversion shocks are generally considered to be of lowto moderate energy level (so as to minimize pain felt by the patient),and/or synchronized with an R-wave and/or pertaining to the treatment oftachycardia. Defibrillation shocks are generally of moderate to highenergy level (i.e., corresponding to thresholds in the range of 4-40joules), delivered asynchronously (since R-waves may be toodisorganized), and pertaining exclusively to the treatment offibrillation. Accordingly, the microcontroller 360 is capable ofcontrolling the synchronous or asynchronous delivery of the shockingpulses.

Insofar as LAP estimation is concerned, the microcontroller includes aconduction delay-based LAP estimation system 401 operative to estimateLAP or other forms of cardiac pressure based on parameters derived fromconduction delays using the techniques described above. That is, theestimation system is operative to: measure an electrical conductiondelay in the heart of the patient and estimate cardiac pressure withinthe patient from the electrical conduction delay. In this example,estimation system 401 includes: an LV-RV delay measurement system 403operative to measure interventricular conduction delays within thepatient and an LV-RV-based LAP estimation system 405 operative toestimated LAP from the measured interventricular delays. The estimationsystem also includes, in this example, an LV-RV-based LV EDV estimationsystem 407 operative to estimate LV EDV from the measuredinterventricular delays and an LV-RV-based LV EDP estimation system 409operative to estimate LV EDP from the measured interventricular delays.Estimation system 401 also includes a re-calibration unit or system 411operative to re-calibrate the conversion factors discussed above. AnLAP-based CHF detection system 415 is provide to detect and track CHFbased on LAP. Warning and/or notification signals are generated, whenappropriate, by a therapy/warning controller 417 then relayed to thebedside monitor 18 via telemetry system 400 or to external programmer402 (or other external calibration system.) Controller 417 can alsocontroller an implantable drug pump, if one is provided, to deliverappropriate medications. Controller 417 also controls the adaptiveadjustment of CRT parameters and other pacing parameters, as discussedabove. Terminals for connecting the implanted warning device and theimplanted drug pump to the pacer/ICD are not separately shown.Diagnostic data pertaining to LAP, CHF, therapy adjustments, etc., isstored in memory 394.

Depending upon the implementation, the various components of themicrocontroller may be implemented as separate software modules or themodules may be combined to permit a single module to perform multiplefunctions. In addition, although shown as being components of themicrocontroller, some or all of these components may be implementedseparately from the microcontroller, using application specificintegrated circuits (ASICs) or the like.

Exemplary External Programmer

FIG. 16 illustrates pertinent components of an external programmer 402for use in programming the pacer/ICD of FIG. 15 and for performing theabove-described calibration techniques. For the sake of completeness,other device programming functions are also described herein. Generally,the programmer permits a physician or other user to program theoperation of the implanted device and to retrieve and displayinformation received from the implanted device such as IEGM data anddevice diagnostic data. Additionally, the external programmer can beoptionally equipped to receive and display electrocardiogram (EKG) datafrom separate external EKG leads that may be attached to the patient.Depending upon the specific programming of the external programmer,programmer 402 may also be capable of processing and analyzing datareceived from the implanted device and from the EKG leads to, forexample, render preliminary diagnosis as to medical conditions of thepatient or to the operations of the implanted device.

Now, considering the components of programmer 402, operations of theprogrammer are controlled by a CPU 502, which may be a generallyprogrammable microprocessor or microcontroller or may be a dedicatedprocessing device such as an application specific integrated circuit(ASIC) or the like. Software instructions to be performed by the CPU areaccessed via an internal bus 504 from a read only memory (ROM) 506 andrandom access memory 530. Additional software may be accessed from ahard drive 508, floppy drive 510, and CD ROM drive 512, or othersuitable permanent mass storage device. Depending upon the specificimplementation, a basic input output system (BIOS) is retrieved from theROM by CPU at power up. Based upon instructions provided in the BIOS,the CPU “boots up” the overall system in accordance withwell-established computer processing techniques.

Once operating, the CPU displays a menu of programming options to theuser via an LCD display 514 or other suitable computer display device.To this end, the CPU may, for example, display a menu of specificprogrammable parameters of the implanted device to be programmed or maydisplay a menu of types of diagnostic data to be retrieved anddisplayed. In response thereto, the physician enters various commandsvia either a touch screen 516 overlaid on the LCD display or through astandard keyboard 518 supplemented by additional custom keys 520, suchas an emergency VVI (EVVI) key. The EVVI key sets the implanted deviceto a safe VVI mode with high pacing outputs. This ensures lifesustaining pacing operation in nearly all situations but by no means isit desirable to leave the implantable device in the EVVI mode at alltimes.

Once all pacing leads are mounted and the pacing device is implanted,the various parameters are programmed. Typically, the physicianinitially controls the programmer 402 to retrieve data stored within anyimplanted devices and to also retrieve EKG data from EKG leads, if any,coupled to the patient. To this end, CPU 502 transmits appropriatesignals to a telemetry subsystem 522, which provides components fordirectly interfacing with the implanted devices, and the EKG leads.Telemetry subsystem 522 includes its own separate CPU 524 forcoordinating the operations of the telemetry subsystem. Main CPU 502 ofprogrammer communicates with telemetry subsystem CPU 524 via internalbus 504. Telemetry subsystem additionally includes a telemetry circuit526 connected to telemetry wand 528, which, in turn, receives andtransmits signals electromagnetically from a telemetry unit of theimplanted device. The telemetry wand is placed over the chest of thepatient near the implanted device to permit reliable transmission ofdata between the telemetry wand and the implanted device. Herein, thetelemetry subsystem is shown as also including an EKG circuit 534 forreceiving surface EKG signals from a surface EKG system 532. In otherimplementations, the EKG circuit is not regarded as a portion of thetelemetry subsystem but is regarded as a separate component.

Typically, at the beginning of the programming session, the externalprogramming device controls the implanted devices via appropriatesignals generated by the telemetry wand to output all previouslyrecorded patient and device diagnostic information. Patient diagnosticinformation includes, for example, recorded IEGM data and statisticalpatient data such as the percentage of paced versus sensed heartbeats.Device diagnostic data includes, for example, information representativeof the operation of the implanted device such as lead impedances,battery voltages, battery recommended replacement time (RRT) informationand the like. Data retrieved from the pacer/ICD also includes the datastored within the recalibration database of the pacer/ICD (assuming thepacer/ICD is equipped to store that data.) Data retrieved from theimplanted devices is stored by external programmer 402 either within arandom access memory (RAM) 530, hard drive 508 or within a floppydiskette placed within floppy drive 510. Additionally, or in thealternative, data may be permanently or semi-permanently stored within acompact disk (CD) or other digital media disk, if the overall system isconfigured with a drive for recording data onto digital media disks,such as a write once read many (WORM) drive.

Once all patient and device diagnostic data previously stored within theimplanted devices is transferred to programmer 402, the implanteddevices may be further controlled to transmit additional data in realtime as it is detected by the implanted devices, such as additional IEGMdata, lead impedance data, and the like. Additionally, or in thealternative, telemetry subsystem 522 receives EKG signals from EKG leads532 via an EKG processing circuit 534. As with data retrieved from theimplanted device itself, signals received from the EKG leads are storedwithin one or more of the storage devices of the external programmer.Typically, EKG leads output analog electrical signals representative ofthe EKG. Accordingly, EKG circuit 534 includes analog to digitalconversion circuitry for converting the signals to digital dataappropriate for further processing within the programmer. Depending uponthe implementation, the EKG circuit may be configured to convert theanalog signals into event record data for ease of processing along withthe event record data retrieved from the implanted device. Typically,signals received from the EKG leads are received and processed in realtime.

Thus, the programmer receives data both from the implanted devices andfrom optional external EKG leads. Data retrieved from the implanteddevices includes parameters representative of the current programmingstate of the implanted devices. Under the control of the physician, theexternal programmer displays the current programmable parameters andpermits the physician to reprogram the parameters. To this end, thephysician enters appropriate commands via any of the aforementionedinput devices and, under control of CPU 502, the programming commandsare converted to specific programmable parameters for transmission tothe implanted devices via telemetry wand 528 to thereby reprogram theimplanted devices. Prior to reprogramming specific parameters, thephysician may control the external programmer to display any or all ofthe data retrieved from the implanted devices or from the EKG leads,including displays of EKGs, IEGMs, and statistical patient information.Any or all of the information displayed by programmer may also beprinted using a printer 536.

Additionally, CPU 502 also preferably includes a conduction delay-basedLAP estimation calibration unit 550 operative to perform the calibrationprocedures described above. CPU 502 also preferably includes aconduction delay-based estimated LAP diagnostics controller 551operative to control the display of estimated LAP values and relateddiagnostics. As already noted, physicians are often more familiar withLAP values than conduction delay values and hence benefit from LAP-baseddiagnostics displays that graphically illustrates changes in LAP withinthe patient, such as changes brought on by heart failure.

Programmer/monitor 402 also includes a modem 538 to permit directtransmission of data to other programmers via the public switchedtelephone network (PSTN) or other interconnection line, such as a TIline or fiber optic cable. Depending upon the implementation, the modemmay be connected directly to internal bus 504 may be connected to theinternal bus via either a parallel port 540 or a serial port 542. Otherperipheral devices may be connected to the external programmer viaparallel port 540 or a serial port 542 as well. Although one of each isshown, a plurality of input output (IO) ports might be provided. Aspeaker 544 is included for providing audible tones to the user, such asa warning beep in the event improper input is provided by the physician.Telemetry subsystem 522 additionally includes an analog output circuit545 for controlling the transmission of analog output signals, such asIEGM signals output to an EKG machine or chart recorder.

With the programmer configured as shown, a physician or other useroperating the external programmer is capable of retrieving, processingand displaying a wide range of information received from the implanteddevices and to reprogram the implanted device if needed. Thedescriptions provided herein with respect to FIG. 16 are intended merelyto provide an overview of the operation of programmer and are notintended to describe in detail every feature of the hardware andsoftware of the programmer and is not intended to provide an exhaustivelist of the functions performed by the programmer.

In the foregoing descriptions, LAP or other cardiac pressure values areestimated from conduction delay values. A variety of techniques were setforth for determining or measuring the delay values. In the followingsection, techniques are set forth for estimating delay values fromadmittance or impedance measurements. Note, though, that the estimateddelay values are not necessarily used to then estimate LAP. Rather, theestimated delay values may be used for any suitable purpose. Inparticular, heart failure may be tracked based on the estimated delayvalues. That is, whereas the foregoing set forth techniques inter aliafor tracking heart failure based on LAP values estimated from measuredconduction delays, the following section sets forth techniques fortracking heart failure based on conduction delays estimated frommeasured impedance or admittance values. The two general techniques maybe used in conjunction, where appropriate.

Admittance/Impedance-Based Delay Estimation Techniques

Turning now to FIGS. 17-20, system and methods for estimating conductiondelays from admittance or impedance values and for tracking heartfailure based on the estimated conduction delays will be brieflysummarized. The examples described here principally exploit measuredimpedance values. However, as impedance in the reciprocal of admittance,measured admittance values can alternatively be exploited. Briefly, withreference to FIG. 17, impedance values are measured at block 600 fromwhich conduction delay values are estimated at block 602. The delayvalues are used to detect heart failure events, at block 604, or toperform heat failure trending. A calibration block is also provided forcalibrating the impedance to delay estimation procedure. That is, whenthe delays are estimated via block 602, supervising personnel can verifythe estimations are correct by comparing the estimated delays toQuickOpt-based delays obtained in the physician's office. Any differencetherebetween can then be used to adjust or calibrated the impedance todelay estimation procedure. Once properly calibrated, impedancemeasurements (block 608) may be used by the pacer/ICD to estimateconduction delays (block 610), from which heat failure events (or heartfailure trends) 612 are detected.

The estimation of conduction delays based on impedance exploits agenerally linear correlation between admittance and conduction timedelays, which is illustrated in FIG. 18 by way of graph 614. Inparticular, the graph shows the relationship between admittance(1/impedance) and VV delay. This example used the impedance vector fromthe LV ring to the RA ring. The delay was the between the RV and LVwhile the RV was being paced. The relationship in this example shows astrong linear relationship between the VV delay and LVring-RAringadmittance in five patients. Line 616 represents the best-fit linebetween W delay and admittance given by: VVdelay [ms]=48.712*Admittance[mS]−4.12.

As explained, heart failure can be detected and tracked based onconduction delays. This is illustrated in FIG. 19 by way of graph 618.In this example, developing heart failure caused an increase in thedelay between the RV and the LV measured when the RV is paced. Day 100represents the normalized time when the five patients experienced a HFexacerbation. HF was resolved at day 104 and then patients recovered.The gray shaded area 620 of the graph highlights the time period whenheart failure was occurring. Hence, FIG. 19 shows that the delayincreased during HF and decreased during recovery. The percent change isreferenced to baseline (i.e. zero percent is no HF). The pacer/ICD canbe programmed to set a threshold (for instance 20%) to detect HF events.If the percent change in the delays increase above 20%, an alarm can beused to trigger the patient to take corrective action.

As shown in FIG. 20, one or multiple impedance or admittance vectors 622can be used in either a linear or multi-linear (i.e. quadratic, etc)combination to estimate the conduction delays. The examples of FIG. 20are as follows: 1: LV ring to RV ring; 2. LV ring to RA ring; 3. RV ringto case; 4. LV ring to case; 5. RA ring to case; and 6. RV coil to case.Multiple different equations can be used to determine the delays. In oneexample, where admittance values are detected, the relationship betweenthe admittance and delay is quadratic:

Delay=α*adm ² +β*adm+δ

where “adm” refer to admittance and where alpha, beta, and gamma areknown constants developed using a training set of data. Multipleadmittance values can be used to determine a delay:

Delay=α₁ *adm ₁ ²+β₁ *adm ₁+α₂ *adm ₂ ²+β₂ *adm ₂+δ

where admittance vectors 1 and 2 with their corresponding parameterswere used to determine the delay. In another embodiment, the estimateddelays can be verified each time the patient goes to the physician'soffice such as with the use of delay algorithm or with special softwaresuch as QuickOpt™. When the device is interrogated with the programmer,the programmer would use the QuickOpt procedure to verify the estimateddelays offline (FIG. 17).

In general, while the invention has been described with reference toparticular embodiments, modifications can be made thereto withoutdeparting from the scope of the invention. Note also that the term“including” as used herein is intended to be inclusive, i.e. “includingbut not limited to”.

APPENDIX A %Setting threshold for find RV max_rv=max(rv);mn_rv=mean(rv); thshld_rv=0.55*(max_rv−mn_rv)+mn_rv; %threshold I findwhere the RV crosses the threshold %Finding when RV crosses thresholdndx=find(rv>thshld_rv); dndx=diff([0; ndx]); sndx=find(dndx>10);strt_ndx=ndx(sndx); dndx=diff([ndx; length(rv)]); endx=find(dndx>10);end_ndx=ndx(endx); I find the maximum signal when the V channel crossesthe threshold, and call that my ndx %Finding maximum for index of RVndx_rv=zeros(length(strt_ndx),1); for i=1:length(strt_ndx) [jnk,mx_ndx]=max(rv(strt_ndx(i):end_ndx(i))); ndx_rv(i)=strt_ndx(i)+mx_ndx−1; end Make sure that each V eventcaptures based on size of signal %Making sure caption occurred bad_ndx=[]; if ndx_lv(end)+25>length(lv)  ndx_lv(end)=[ ]; end fori=1:length(ndx_lv)  mx_lv=max(lv(ndx_lv(i):ndx_lv(i)+12));  if mx_lv<69  bad_ndx=[bad_ndx i];  end end ndx_lv(bad_ndx)=[ ]; This next sectionaligns the LV with the RV to match sure they are matched with eachother%Making sure LV and RV are same length if ~isempty(ndx_lv) &&~isempty(ndx_rv)  if length(ndx_rv)~=length(ndx_lv)   whilendx_rv(1)<ndx_lv(1)    ndx_rv(1)=[ ];   end   whilendx_lv(end)>ndx_rv(end)    ndx_lv(end)=[ ];   end  end end iflength(ndx_rv)~=length(ndx_lv)  %disp(‘error: RV ~= LV: LV’)  %RemovingT waves from RV ndx  diff_rv=diff(ndx_rv);  diff_ndx=find(diff_rv<100); ddndx=diff([0;diff_ndx]);  diff_ndx=diff_ndx(ddndx~=1); ndx_rv(diff_ndx+1)=[ ];  %Aligning RV with LV indices  iflength(ndx_rv)<length(ndx_lv)   tmp_ndx=zeros(length(ndx_rv),1);  bad_ndx=[ ];   for i=1:length(ndx_rv)    tmp=find(ndx_lv>ndx_rv(i)−56& ndx_lv<ndx_rv(i)+90);    if ~isempty(tmp)     if length(tmp)>1     tmp2=ndx_lv(tmp)−ndx_rv(i);      [jnk,tmp3]=min(abs(tmp2));      tmp=tmp(tmp3);      end      tmp_ndx(i)=ndx_lv(tmp);     else     bad_ndx=[bad_ndx i];     end    end    ndx_rv(bad_ndx)=[ ];   ndx_lv=tmp_ndx;    ndx_lv(ndx_lv==0)=[ ];   elseiflength(ndx_rv)>length(ndx_lv)    tmp_ndx=zeros(length(ndx_lv),1);   bad_ndx=[ ];    for i=1:length(ndx_lv)    tmp=find(ndx_rv>ndx_lv(i)−80 & ndx_rv<ndx_lv(i)+80);     if~isempty(tmp)      if length(tmp)>1       tmp2=ndx_rv(tmp)−ndx_lv(i);      [jnk,tmp3]=min(abs(tmp2));       tmp=tmp(tmp3);      end     tmp_ndx(i)=ndx_rv(tmp);     else      bad_ndx=[bad_ndx i];     end   end    ndx_lv(bad_ndx)=[ ];    ndx_rv=tmp_ndx;    ndx_rv(ndx_rv==0)=[];   end end

1. A method for controlling a therapy delivered to a patient using animplantable medical device, the method comprising: measuring anelectrical conduction delay in the heart of the patient that is affectedby cardiac pressure; estimating cardiac pressure within the patient fromthe electrical conduction delay; and controlling a therapy for thepatient based on estimated cardiac pressure.
 2. The method of claim 1wherein the implantable device is equipped with an implantable drug pumpand wherein drug therapy is controlled based on estimated cardiacpressure.
 3. The method of claim 1 wherein therapy is controlled in aneffort to maintain the estimated cardiac pressure within a predeterminedrange representative of healthy pressure values.
 4. The method of claim3 wherein, so long as the estimated cardiac pressure is within thepredetermined range representative of healthy pressure values, notherapy adjustments are performed.
 5. The method of claim 3 wherein, ifthe estimated cardiac pressure is within a first predetermined rangeabove healthy pressure values, cardiac pacing parameters are adjusted inan effort to lower the cardiac pressure.
 6. The method of claim 5wherein, if the estimated cardiac pressure is within a secondpredetermined range above the first range, one or more of the followingactions are performed: warning signals are generated indicative of highpressure values; appropriate medications are directly delivered to thepatient; instruction signals are generated to instruct the patient totake appropriate medications; instruction signals are generated toinstruct the patient to visit a physician.
 7. The method of claim 1wherein the step of adjusting a therapy includes adjusting one or morepacing timing parameters of the implantable medical device to reducecardiac pressure.
 8. The method of claim 7 wherein therapy is adjustedby adjusting an atrioventricular (AV) timing parameter.
 9. The method ofclaim 7 wherein therapy is adjusted by adjusting an interventricular(LV-RV) timing parameter.
 10. The method of claim 7 wherein therapy isadjusted by adjusting an intraventricular (LV₁-LV₂, RV₁-RV₂) timingparameter.
 11. The method of claim 7 wherein therapy is adjusted basedon pressure values estimated only during particular patient activitylevels as determined in conjunction with an activity sensor.
 12. Themethod of claim 7 wherein therapy is adjusted based on pressure valuesestimated only while the patient is in a particular posture asdetermined in conjunction with a position sensor.
 13. The method ofclaim 7 wherein therapy is adjusted based on pressure values estimatedonly while the patient has a particular blood oxygen saturation level asdetermined in conjunction with a blood oxygen saturation sensor.
 14. Themethod of claim 7 wherein therapy is adjusted on a beat-by-beat basis.15. The method of claim 7 wherein the device is equipped to selectivelydeliver pacing at any of a plurality of pacing sites and wherein thestep of adjusting therapy is performed to select particular pacing sitesbased on the conduction delays.
 16. A system for controlling therapydelivered to a patient using an implantable medical device, the systemcomprising: an electrical conduction delay measurement unit operative tomeasure conduction delays within the heart of the patient that areaffected by cardiac pressure; a cardiac pressure estimation unitoperative to estimate cardiac pressure within the patient based on theelectrical conduction delay; and a therapy controller operative tocontrol therapy based on estimated cardiac pressure.
 17. The system ofclaim 16 wherein the therapy controller is operative to control therapyin an effort to maintain the estimated cardiac pressure within apredetermined range representative of healthy pressure values.
 18. Thesystem of claim 17 wherein, so long as the estimated cardiac pressure iswithin the predetermined range representative of healthy pressurevalues, the therapy controller makes no therapy adjustments based on theestimated cardiac pressure.
 19. The system of claim 18 wherein, if theestimated cardiac pressure is within a first predetermined range abovehealthy pressure values, the therapy controller is operative to adjustcardiac pacing parameters in an effort to lower the cardiac pressure.20. The system of claim 19 wherein, if the estimated cardiac pressure iswithin a second predetermined range above the first range, the therapycontroller is operative to perform one or more of the following actions:generate warning signals indicative of high pressure values; deliverappropriate medications directly to the patient via an implantable drugpump; generate instruction signals for transmitting to an externaldevice for instructing the patient to take appropriate medications;generate instruction signals for transmitting to an external device forinstructing the patient to visit a physician.
 21. A method for detectinga heart failure condition within a patient using an implantable medicaldevice, the method comprising: measuring an electrical conduction delayin the heart of the patient that is affected by cardiac pressure;estimating cardiac pressure within the patient from the electricalconduction delay; and detecting a heart failure condition based onestimated cardiac pressure.
 22. The method of claim 21 wherein theimplantable device is equipped with a warning device and wherein awarning is generated upon detection of heart failure.
 23. The method ofclaim 22 wherein the implantable device is equipped to transmit signalsto an external display device and wherein the warning is transmitted tothe external device.
 24. A method for estimating cardiac pressure withina patient using an implantable medical device, the method comprising:measuring an electrical conduction delay in the heart of the patient;estimating cardiac pressure within the patient from the electricalconduction delay; and transmitting estimated cardiac pressure values toan external device.
 25. The method of claim 24 wherein the externaldevice is equipped to store estimated cardiac pressure values within adatabase.
 26. The method of claim 24 wherein the implantable device isequipped to receive signals from the external device and whereinadjusted pacing parameters are received from the external device. 27.The method of claim 25 wherein the adjusted pacing parameters includecardiac resynchronization (CRT) parameters.